Letters to the Editors

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1 Letters to the Editors Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. They should not exceed 1000 words (excluding references) and may be subject to editing or abridgment. Please submit letters in duplicate, typed double-spaced. Include a fax number for the corresponding author and a completed copyright transfer agreement form (published in the January and July issues). Intra-arterial Pro-urokinase in Ischemic Stroke Dr del Zoppo et al are to be congratulated for successfully completing the first randomized, double-blind, controlled trial of intra-arterial pro-urokinase (pro-uk) in ischemic stroke (PRO- ACT). 1 A sophisticated route of administration of pro-uk by microcatheter into the thrombus was chosen in order to maximize lysis and minimize hemorrhagic side effects. Moreover, at the low infusion rate (6 mg over 2 hours) that was used, there is no systemic conversion of pro-uk to urokinase, and its effect is entirely fibrin specific. As a result, little or no bleeding should have occurred, because in stroke, bleeding is correlated with nonspecificity (ie, streptokinase induces more bleeding than tpa). In view of this prudent protocol, it is curious that intravenous heparin was given concomitantly with pro-uk in the treatment group or given alone in the placebo group. Early anticoagulation with heparin for ischemic stroke has long been considered hazardous, and it has been recommended that heparin be delayed for at least 48 hours after embolism. 2 Even when heparin was administered by the subcutaneous route to patients with ischemic stroke, a 4-fold increase in hemorrhagic stroke was reported in the International Stroke Trial. 3 Consequently, heparin has been scrupulously avoided in all of the clinical trials of tpa in stroke. Therefore, it is not surprising that in the PROACT study, a 15% incidence of intracranial bleeding occurred and more than a 3-fold increase in hemorrhagic stroke was observed when pro-uk was combined with a higher dose of heparin compared with a lower dose. Since no significant difference was seen in the two placebo groups given the two doses of heparin alone, it was the adjunctive heparin which was probably largely responsible for the hemorrhagic strokes in this study. The rationale for using heparin in this study was based on previous observations that heparin augments the thrombolytic effect of pro-uk. 4,5 Indeed a doubling of the recanalization rate at the higher dose of heparin was found (82% versus 40%) in the PROACT study, confirming the previous data that heparin significantly promotes thrombolysis by pro-uk. The question then is this: can this beneficial effect of heparin be preserved without incurring the risk of concomitant administration with pro-uk? Heparin has no promoting effect on clot lysis in a plasma milieu by either pro-uk or tpa in vitro. Therefore, heparin is not integral to clot lysis by pro-uk and is related to certain in vivo effects. Several mechanisms have been proposed. First, thrombolysis with tpa can induce certain procoagulant effects that are reversible by heparin. However, in contrast to tpa, this was not the case when coronary thrombolysis was induced by pro-uk, 6 so this problem can be excluded when pro-uk is used. Second, thrombin inactivates pro-uk. 7 Therefore, neutralizing the thrombus-bound thrombin by heparin has been postulated to be responsible for its augmentation of pro-uk induced thrombolysis. 5 Third, heparin induces the release of tpa from endothelial cells, and a 2- to 3-fold increase in plasma tpa antigen levels has been reported after intravenous heparin. 8 This heparin effect is relevant, because tpa and pro-uk are synergistic in fibrinolysis 9 and an initial small bolus of tpa has been shown to strongly promote coronary thrombolysis by pro-uk Finally, although some binding of heparin to plasminogen and pro-uk has also been reported, there is no evidence that this property of heparin promotes clot lysis. Thrombin neutralization and/or tpa release are, therefore, the most likely effects of heparin responsible for its promotion of thrombolysis by pro-uk. These beneficial effects could probably be fully achieved by a single bolus of heparin given prior to the pro-uk infusion. The authors stated that a new study involving 180 patients given 9 mg pro-uk intra-arterially is now in progress. It would be most unfortunate if the potential benefits of reperfusion by pro-uk are needlessly undermined by a concomitant infusion of heparin that causes bleeding into the infarct zone. Victor Gurewich, MD, FACP Jian-ning Liu, PhD Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts 1. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M, and the PROACT Investigators. PROACT: a phase II randomized trial of recombinant prourokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke. 1998;29: Shields RW Jr, Laureno R, Lachman T, Victor M. Anticoagulant-related hemorrhage in acute cerebral embolism. Stroke. 1984;15: International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19,435 patients with acute ischaemic stroke. Lancet. 1997; 349: Burke SE, Lubbers NL, Nelson RA, Henkin J. Recombinant prourokinase requires heparin for optimal clot lysis and restoration of blood flow in a canine femoral artery thrombosis model. Thromb Haemost. 1993;69: Tebbe U, Windeler J, Boesl I, Hoffmann H, Wojcik J, Ashmawy M, Schwarz ER, von Loewis P, Rosemeyer P, Hopkins G, Barth H, on behalf of the LIMITS Study Group. Thrombolysis with recombinant unglycosylated single-chain urokinase-type plasminogen activator (saruplase) in acute myocardial infarction: influence of heparin on early patency rate (LIMITS Study). J Am Coll Cardiol. 1995;26: Weaver WD, Hartmann JR, Anderson JL, Reddy PS, Sobolski JC, Sasahara AA. New recombinant glycosylated prourokinase for treatment of patients with acute myocardial infarction. J Am Coll Cardiol. 1994; 24: Gurewich V, Pannell R. Inactivation of single chain urokinase (prourokinase) by thrombin and thrombin-like enzymes: relevance of the finding to the interpretation of fibrin binding experiments. Blood. 1987; 69: Huber K, Resch I, Rosc D, Probst P, Kaindl F, Binder BR. Heparininduced increase of t-pa antigen plasma levels in patients with unstable angina: no evidence for clinical benefit of heparinization during the initial phase of treatment. Thromb Res. 1989;55: Pannell R, Black J, Gurewich V. The complementary modes of action of tissue plasminogen activator (t-pa) and pro-urokinase (pro-uk) by which their synergistic effect on clot lysis may be explained. J Clin Invest. 1988;81: Zarich SW, Kowalchuk GJ, Weaver WD, Loscalzo J, Sassower M, Manzo K, Byrnes C, Muller JE, Gurewich V, for the PATENT Study Group. Sequential combination thrombolytic therapy for acute myocardial infarction: results of the pro-urokinase and t-pa enhancement of thrombolysis (PATENT) trial. J Am Coll Cardiol. 1995;26: Response We are grateful to Drs Gurewich and Liu for raising several interesting and important issues regarding our first report of a randomized, double-blind, controlled trial of intra-arterial pro-

2 1256 Letters to the Editor urokinase (rpro-uk) in ischemic stroke (PROACT). 1 The use of heparin anticoagulation in this study had a significant impact on both recanalization efficacy and hemorrhagic transformation. The interactions between pro-urokinase and heparin both in vitro and in vivo were indeed known to us during the trial design period. The heparin dosing was not adjusted for the purposes of augmenting pro-uk activity, however. A range of heparin dosages and infusion schedules are used for diagnostic angiography and microcatheter placement currently, but no consensus exists. The heparin dose rates are often chosen empirically. In discussion among the neurointerventional collaborators in this project, it was decided that a heparin dose of 100 IU/kg bolus (maximum, IU) followed by 1000 IU/h intravenous infusion for 4 hours would be adequate to prevent catheterdependent thrombosis. However, during the early stages of the trial, the frequency of hemorrhagic transformation suggested that the heparin dosing be examined more carefully. The subsequent decrease in heparin dose was accompanied by a decrease in hemorrhage and recanalization efficacy. 1 Albeit with low numbers of patients, the frequency of symptomatic brain hemorrhage in the low heparin dose cohort (6.7%) was not apparently different from that of intravenous rtpa in the National Institutes of Neurological Diseases and Stroke study, 2 despite a longer time to treatment and the inclusion of proximal middle cerebral artery strokes in PROACT. From that experience and the known in vivo effects of rpro-uk and heparin in other arenas indicated by Drs Gurewich and Liu, we would concur that dosing of heparin in the face of rpro-uk infusions in the central nervous system must be performed with caution. The heparin dosing for PROACT II, the follow-on trial of intra-arterial infusion of 9 mg rpro-uk in 180 patients now in progress, also attempts to balance the risk of hemorrhage and efficacy benefit. Here, a higher dose of rpro-uk (9 mg) has been combined with the lower dose rate of heparin used in PROACT (2000 IU bolus followed by 500 IU/h for 4 hours). As of late February 1998, 146 patients have been recruited, for whom hemorrhagic transformation and serious adverse events, carefully monitored by the External Safety Committee, have thus far not exceeded prospectively established safety rules. We concur with Drs Gurewich and Liu that care must be taken to restrict the dosage of heparin to prevent untoward complicating ischemia-related hemorrhages with rpro-uk but not to allow catheter-related thrombosis. Gregory J. del Zoppo, MD The Scripps Research Institute Randall T. Higashida, MD University of California, San Francisco Anthony J. Furlan, MD The Cleveland Clinic Foundation Howard A. Rowley, MD University of California, San Francisco Michael Gent, DSc Hamilton Civic Hospitals Research Centre and the PROACT Investigators 1. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M, and the PROACT Investigators. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke. 1998;29: The NINDS rt-pa Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333: Clinical Trials and Financial Reimbursement Randomized clinical trials are the current gold standard for scientifically establishing the effectiveness of new therapies in medicine. Clinical investigators choose to participate in research studies for several reasons. The reasons are not mutually exclusive, and they include the following: (1) contribution to medical advances, (2) academic recognition, and (3) financial renumeration. 1 The Asymptomatic Carotid Surgery Trial (ACST) is an international clinical trial evaluating the effectiveness of carotid endarterectomy for the prevention of stroke in patients with asymptomatic carotid artery stenosis. 2 As part of the trial s recent expansion to sites in North America, 60 leading academic neurology centers in the United States were invited to join the study. Representatives from 32 centers (53%) responded to the initial mailing and sought additional information regarding the trial. Two centers declined to participate on the basis of concerns regarding measurement of carotid stenosis. The majority of centers refused to join the study because of the lack of any per patient financial reimbursement. One center commented that they were looking for the clinical trial that would deliver the golden egg. These responses from preeminent neurological academic programs led me to the following conclusions: (1) there is considerable uncertainty regarding the value of carotid endarterectomy for asymptomatic stenosis among US stroke specialists, and (2) decisions regarding which clinical trials to participate in are to a large extent based on the potential for financial rewards. Ideally, one would hope that clinicians would participate in a clinical research study on the basis of science and whether the clinical problem being addressed is a burning issue. It appears, however, that in the current financial climate of academic medical centers in the United States, science is taking a backseat to dollars in some instances. Seemant Chaturvedi, MD Wayne State University Detroit, Michigan United States Coordinator, ACST 1. Saver JL. Coping with an embarrassment of riches: how stroke centers may participate in multiple, concurrent clinical stroke trials. Stroke. 1995;26: Halliday AW. The Asymptomatic Carotid Surgery Trial (ACST): rationale and design. Eur J Vasc Surg. 1994;8: High-Dose Tirilazad for Acute Stroke (RANTTAS II) In a previous communication in Stroke, 1 we reported lack of efficacy of tirilazad mesylate (6 mg/kg per day for 3 days) in patients with acute ischemic stroke treated within 6 hours in North American centers and hypothesized that the lack of benefit may have been secondary to an inadequate dose, especially in females. Studies testing higher doses in both males (12.5 mg/kg on the first day, then 10 mg/kg/d for 2 days) and females (15 mg/kg on the first day, then 12 mg/kg/d) were begun. This letter reports a synopsis of results of the high-dose study in North American (RANTTAS II), which was prematurely stopped by the sponsor when questions regarding safety emerged from a parallel study in Europe (TESS II). One hundred twenty-six (14% of the planned sample size) patients were enrolled in RANTTAS II within 4 hours of the onset of symptoms. Of these, 111 were fully eligible patients with ischemic stroke: 53 in the tirilazad group, and 58 in the vehicle group. There was an approximate balance in the baseline characteristics of the patients in each treatment group; the median entry NIH Stroke Scale score was 12 in the tirilazad group and 13 in the placebo group. The Table shows the results of the primary end point measurement, the Barthel Index at 3 months.

3 Letters to the Editor Month Outcome by Barthel Index Score of Fully Eligible Patients (n 53) Overall Male Female (n 58) (n 30) (n 33) (n 23) (n 25) Fully independent, Barthel 100, n (%) 16 (30%) 18 (31%) 10 (33%) 11 (33%) 6 (26%) 7 (28%) Near independence, Barthel 85 95, n (%) 12 (23%) 5 (9%) 8 (27%) 2 (6%) 4 (17%) 3 (12%) Assisted independence, Barthel 60 80, n (%) 6 (11%) 4 (7%) 3 (10%) 3 (9%) 3 (13%) 1 (4%) Dependent, Barthel 25 55, n (%) 8 (15%) 7 (12%) 4 (13%) 4 (12%) 4 (17%) 3 (12%) Severely dependent, Barthel 0 20, n (%) 1 (2%) 5 (9%) 0 2 (6%) 1 (4%) 3 (12%) Dead, n (%) 10 (19%) 19 (33%) 5 (17%) 11 (33%) 5 (22%) 8 (32%) Adjusted odds ratio* (95% confidence interval) 0.84 ( ) 0.6 ( ) 1.14 ( ) Adjusted for age, gender, baseline NIH-SS. n indicates number of patients. *Odds ratio of 1 favors tirilazad vs vehicle. The high doses of tirilazad and vehicle were reasonably well tolerated, though the incidence of drug-related infusion site disorders was fairly high in both groups (46% tirilazad, 24% vehicle). No fully eligible patient had premature termination of the study drug because of perceived intolerance of the medication. To summarize, tirilazad treatment of fully eligible stroke patients was associated with an absolute reduction in mortality of 14% and an increase in the proportion of patients who were independent (Barthel Index score of 60) at 3 months. The potential benefits were observed in both men and women. The observed differences were not statistically significant, however, and need to be confirmed in a larger study. No evidence for harm emerged from this experience. E. Clarke Haley, Jr, MD On behalf of the RANTTAS II Investigators University of Virginia Health System Charlottesville, Virginia This study was sponsored by Pharmacia & Upjohn, Inc. 1. The RANTTAS Investigators: A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). Stroke. 1996;27: Differences in Stroke Between White, Hispanic, and Native American Patients: A Correction Upon review of our published article, Differences in Stroke Between White, Hispanic, and Native American Patients: The Barrow Neurological Institute Stroke Database (Stroke. 1998:29 33), we note that we misstated a historical fact. On page 32, paragraph 2, we stated that Native Americans are thought to have migrated to this continent from eastern Asia via the arctic regions of western Canada between the thirteenth and sixteenth centuries. In our original manuscript we had stated that Hispanics migrated to this continent between the thirteenth and sixteenth centuries. Part of this statement became misplaced during the manuscript revision process. The correct facts are these: (1) Native Americans migrated to this continent many thousands of years ago; (2) Hispanics migrated to this continent between the thirteenth and sixteenth centuries. We apologize for our proofreading oversight. James L. Frey, MD Heidi K. Jahnke, RN, BSN Division of Neurology Barrow Neurological Institute Phoenix, Arizona Endothelins in Acute Ischemic Stroke I read with interest the recently published article by Lampl et al. 1 Because we have also investigated the role of endothelin in acute cerebrovascular accidents, some comments on their data may highlight the problematic role of the endothelins in acute stroke patients. Lampl et al emphasize the role of an elevation of cerebrospinal fluid (CSF) endothelin-1 (ET-1), whereas the plasma values did not show any significant changes. In their 1992 article, 2 the same author group demonstrated a relevance of ET-1 plasma levels. There was a 4-fold increase in the plasma ET-1, especially during the first 24 hours after stroke. The authors do not offer an explanation for these somewhat contradictory results. They offer the very early time point of the measurement in their recent study compared with previous findings. However, in their 1992 study 2 the early patients actually had the highest ET-1 plasma levels. The other offered explanation that the plasma ET-1 level in the control group was extremely high, thus preventing statistically significant results for the plasma ET-1 levels is a problem that is very difficult to handle. It is obvious that the control group in the 1997 study has a mean plasma ET-1 level 2-fold higher than those in 1992, but this major difference may only emphasize the extreme variability of the measurement or variability between healthy controls. Actually, one may argue that the results in the 1992 study were less significant or even not significant compared with those in the 1997 control group. Our own group published results concerning big endothelin-1 (BET-1), the precursor of ET-1, in acute ischemic stroke. 3 There was no overall elevation in plasma BET-1. Differences between patients with larger or smaller infarctions may reflect more an indicator function for the amount of damaged brain than a pathophysiological role. 3 The authors claimed to be the first to report CSF ET-1 levels in acute ischemic stroke. However, in 1990 Suzuki et al 4 described 2 patients with acute ischemic stroke who had already CSF ET-1 determination. This group did not find any elevation of ET-1 in CSF after acute stroke. They even used these 2 patients as controls for elevated ET-1 CSF samples from patients with SAH. Interestingly, Lampl et al 1 cited another work of Suzuki et al 5 twice (as references 18 and 32) in their 1997 paper but failed to refer to the study with the CSF ET-1 values in 2 stroke patients. The authors cited our own article 6 from 1994 incorrectly. This study showed no significant changes in BET-1 in patients suffering from acute intracerebral hemorrhage. The authors cited this paper in such a way that the reader may think it has shown elevated ET-1 in acute subarachnoid hemorrhage. Considering all the different studies together, 1 6 it might be more appropriate to conclude that there is no consistent pattern of

4 1258 Letters to the Editor endothelin elevation after acute ischemic stroke. Increased levels of ET-1 may reflect the degree of tissue damage rather than a pathophysiological role. This may also be discussed in subarachnoid hemorrhage. 7 One may obviously suspect a possible deleterious role of ET-1 in acute ischemic stroke, because the constrictive mode in vasoregulation is mediated by ET-1. However, the data from clinical studies from which one may draw conclusions are too weak to establish the experimentally proposed relationship between endothelin elevation and secondary vasoconstriction/ischemia in acute stroke patients. Dr Gerhard F. Hamann, PD Ludwig-Maximilians-University Klinikum Großhadern Munich, Germany 1. Lampl Y, Fleminger G, Gilad R, Galron R, Savora-Pinhas I, Sokolovsky M. Endothelin in cerebrospinal fluid and plasma of patients in the early stage of ischemic stroke. Stroke. 1997;28: Ziv I, Fleminger G, Dyaldetti R, Achiron A, Melamed E, Sokolovsky M. Increased plasma endothelin 1 in acute stroke. Stroke. 1992;23: Hamann GF, Isenberg E, Strittmatter M, Moili R, Schimrigk K. Bigendothelin in acute ischemic stroke. J Stroke Cerebrovasc Dis. 1993;3: Suzuki H, Sato S, Suzuki Y, Oka M, Tsuchiya T, Iino I, Yamanaka T, Isgihara N, Shimoda S. Endothelin immunoreactivity in CSF of patients with subarachnoid haemorrhage. Ann Med. 1990;22: Suzuki H, Sato S, Suzuki Y, Takekoshi K, Ishihara N, Shimoda S. Increased endothelin concentration in CSF from patients with subarachnoid hemorrhage. Acta Neurol Scand. 1990;81: Hamann GF, Isenberg E, Strittmatter M, Stoll M, Keshevar T, Moiili R, Schimrigk K. Big endothelin in spontaneous intracerebral hemorrhage. Eur Neurol. 1994;34: Hamann GF, Schimrigk K. What is the relevance of the endothelins in subarachnoid haemorrhage? J Neurol Neurosurg Psychiatry. 1995;58:392. Training as a Prerequisite for Reliable Use of NIH Stroke Scale Before new therapies for ischemic stroke are established, their safety and effectiveness must be proved. In particular, the numerous multicenter acute stroke trials currently being performed require a valid, efficient, and reliable measure of patient status and outcome after treatment. Interrater variation in the assessment of neurological deficits could imply that important effects of the treatment remain concealed, which in turn may have a misleading influence on therapeutic decisions. A commonly used yardstick for measuring the outcome of neurological deficits in stroke patients is the National Institutes of Health Stroke Scale (NIHSS). 1 3 Not only experienced neurologists can reliably apply the NIHSS; it can be used as well by nonneurologists or even nonphysicians (eg, study nurses), 4 7 provided the raters are well trained and given detailed instructions. As far as the NINDS study is concerned, the investigators were video trained and required to take an examination. 1 The question, however, of whether the NIHSS provides precise and reliable data when applied without an intensive training program has not yet been raised. We therefore investigated the reliability of the NIHSS as used by trained and untrained raters in 22 stroke patients in the Neurological Department at the University Hospital of Cologne. Diagnosis was confirmed by CT. Eighteen patients were suffering from ischemic and 4 from hemorrhagic stroke; 3 of the strokes were infratentorial and 19 supratentorial; 13 lesions were left and 6 right hemispheric. Five patients were obtunded or comatose, and 5 suffered from severe aphasia. Four neurologists in our department independently assessed the patients neurological status. Two raters were experienced in using the NIHSS, video trained and instructed by the material of the NINDS-group (available from B.C. Tilley, PhD, Biostatistics and Research Epidemiology, Henry Ford Health Science Center, 1 Ford Place, Suite 3E, Detroit, MI 48202). The other two were inexperienced in the application of the NIHSS and were given no information other than the original NIHSS examination form. In this form the instructions for rating are very short and do not go into detail on how to handle problematic cases, such as aphasic, comatose, or unresponsive patients. To minimize a possible bias from a training or fatigue effect in the patients, untrained and trained raters were assigned in random order. To reduce the impact of fluctuation on the patients neurological state, evaluation had to be performed within a close time window ( 90 minutes) only in the state of subacute stroke ( 12 hours after symptom onset). 5 To assess interobserver reliability, the statistic was used for every individual item to be examined with use of SPSS for Windows 7.0 (SPSS Inc) and BMDP 7.0 Dynamic (BMDP Statistical Software, Inc). The degree of interrater agreement based on is considered excellent if 0.80, substantial if is between 0.61 and 0.80, moderate if between 0.41 and 0.60, fair if between 0.21 and 0.40, and slight or poor if Additionally, we compared the total scores because they are generally used for assessment of outcome in clinical studies. However, this is not strictly valid, because the NIHSS does not represent a collection of numerical ratings but rather one of ordinal ratings. 7 The results regarding the reliability achieved among trained raters with mean 0.61 (SD 0.17) show substantial interrater reliability. As far as the untrained group is concerned, was 0.33 (SD 0.22), indicating fair interrater reliability. Between trained and untrained raters, the unweighted was 0.45 (SD 0.2), indicating moderate agreement. Thus, the reliability achieved among untrained raters and that achieved among trained and untrained raters is substantially poorer than the result achieved among trained raters. Furthermore, reliability of individual items differed substantially between trained and untrained raters. Among trained raters, fair agreement was found only in 2 items, limb ataxia ( 0.34) and neglect ( 0.32); there were no items with poor agreement. Among the untrained raters, the items ataxia ( 0.03), gaze ( 0.06), visual fields ( 0.02), and dysarthria ( 0.18) were poorly reliable; furthermore, 6 items were only fairly reliable. The mean total score for the trained raters was (SD 10.02; range, 2 to 40); the maximum difference between scores was 3 points in 5 patients, 2 points in 4 patients, and 1 point in 7 patients. Identical score was reached in 5 patients (1 missing). Among untrained raters, the maximum difference was 10 points, and a difference of 4 points was found in 4 patients. Between trained and untrained raters, the difference of total scores reached 4 points in 12 patients. The results of the present study suggest that good interrater reliability of the NIHSS 3 7 depends on adequate training of the raters. Interobserver reliability among trained raters was substantial, with a mean of 0.61, which is comparable to prior study results ( between 0.51 and 0.69). 3 7 By contrast, only fair reliability was achieved among untrained raters ( 0.33). The discrepancies in interobserver reliability achieved among untrained observers and among untrained and trained observers ( 0.45) are alarming. They might not only influence study results but also therapeutical decisions. Especially in a large multicenter trial effected on an international basis with numerous raters of different countries, high reliability of the assessment score as a primary outcome measure is crucial. Our study demonstrates that even within one and the same department only fair reliability can be reached without an adequate training program. Apart from the difficulties in the assessment of some individual items, as reported in former studies, 3 7 one of the major problems the group of the untrained raters faced was the lack of instruction necessary for assessment of the 10 comatose, obtunded, unresponsive, and aphasic patients. In 8 of these patients,

5 Letters to the Editor 1259 there were substantial differences ( 4 or more points) in total scores between trained and untrained raters, because assessment of several individual items such as gaze, visual fields, and dysarthria in those patients is especially problematic if no detailed instruction is provided. In conclusion, without any systematic training program and knowledge of detailed instructions, the NIHSS can not reliably be applied. Therefore, a standardized use of the NIHSS is mandatory. Susanne Schmülling, MD Martin Grond, MD Jobst Rudolf, MD Klinik und Poliklinik für Neurologie Universität zu Köln Peter Kiencke Institut für Medizinische Statistik, Informatik und Epidemiologie Universität zu Köln Köln, Germany 1. The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333: Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerici M, for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA. 1995;274: Albanese MA, Clarke WR, Adams HP, Woolson RF, and TOAST Investigators. Ensuring reliability of outcome measures in multicenter clinical trials of treatments for acute ischemic stroke. Stroke. 1994;25: Brott T, Adams HP, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, Rorick M, Moomaw CJ, Walker M. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20: Goldstein LB, Bartels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol. 1989;46: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale: extension to non-neurologists in the context of a clinical trial. Stroke. 1997;28: Lyden P, Brott T, Tilley B, Welch KMA, Mascha EJ, Levine S, Haley EC, Grotta J, Marler J, and the NINDS TPA Stroke Study Group. Improved reliability of the NIH Stroke Scale using video training. Stroke. 1994;25: Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33: