(Circulation. 2007;115:2602-2605.)
© 2007 American Heart Association, Inc.
Editorial |
From the Department of Molecular and Experimental Medicine (G.J.d.Z., J.A.K.) and Division of Biomathematics (J.A.K.), The Scripps Research Institute, La Jolla, Calif.
Correspondence to Gregory J. del Zoppo, MD, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, MEM-132, La Jolla, CA 92037. E-mail grgdlzop{at}scripps.edu
Key Words: Editorials angiography cerebrovascular circulation reperfusion stroke ultrasonics
| Introduction |
|---|
|
|
|---|
Article p 2660
| Recanalization of Cerebral Arteries Improves Outcome |
|---|
|
|
|---|
The use of clinical assessment scales for stroke outcome is one of the very interesting issues raised by the article by Mikulik and colleagues in this issue of Circulation.7 Data from the Combined Lysis of Thrombus in Brain Ischemia Using Transcranial Ultrasound and Systemic t-PA (CLOTBUST) trial were reexamined to compare outcome according to the National Institutes of Neurological Disorders and Stroke (NIHSS) stroke scale, an ordinal scale, with apparent recanalization by transcranial Doppler (TCD) ultrasonography. Data from the phase I feasibility study (of transmitted ultrasound thrombus disruption with systemic rt-PA) and the phase II CLOTBUST trial have been reported previously in several forms.8,9 This post hoc analysis suggests that a relationship exists between NIHSS score and TCD evidence of recanalization and that this relationship can be optimized by seeking a threshold score change that reflects improvement. Perhaps the most important aspect of this data analysis is the attempt to quantify a relationship between recanalization of a cerebral artery and its impact on neurological function. There are several premises inherent in this analysis: (1) the relationship between TCD and angiography in detecting both patent and occluded cerebral arteries, (2) assessment of recanalization in the acute setting, (3) the relationship of ordinal scales to the observed deficits, and (4) the effective sensitivity of such scales to change in neurological outcome.
| Cerebral Angiography and TCD in the Acute Setting |
|---|
|
|
|---|
90 and 174 minutes after stroke onset, respectively) after stroke.17 The ability of TCD to reliably detect acutely occluded cerebral arteries is only now being studied consistently. Recently, suggested "practice standards" have provided insonation depths for individual cerebral arteries and their anticipated waveforms, but use acutely in stroke is not yet addressed.18 The limitations of TCD in this setting are the requirement for a proper bone window in a nonagitated patient and experience. There is still insufficient experience with these procedures in stroke in the broader context beyond centers with real capability, which makes use of TCD in proper hands to define the occlusion status of a proximal artery segment in acceptable patients suffering an ischemic stroke forward-looking but not the standard.
| Outcome Scales in Stroke |
|---|
|
|
|---|
Another feature of the NIHSS is its specific limitation to the anterior or carotid artery circulation. Injury to brain stem functions from occlusions of the vertebral-basilar artery system are not readily captured by this scale. The bigger issue is how to handle the composite score represented by the NIHSS and similar scoring instruments. We describe our patients in terms of their deficits, but studies require a summary description or score. Among the useful observations with the summary score is how different stroke subtypes behave. Wityk et al20 studied 50 ischemic stroke patients treated with conventional therapy and found that the NIHSS scores of patients with lacunar infarcts did not significantly improve by day 10, in contrast to patients with middle cerebral artery territory emboli. Furthermore, the baseline NIHSS score indicates ultimate outcome (in the absence of reperfusion).21 In the setting of rt-PA exposure, the best outcomes occurred in patients with baseline NIHSS scores of 10 to 14 compared with placebo treatment.22 Curiously, among 3 prospective, controlled, and blinded trials of rt-PA treatment in acute ischemic stroke patients, before 3 or 6 hours from symptom onset, outcome was quite different despite nearly identical baseline NIHSS scores (median, 13 to 14).2224 The reasons have not been easy to figure out but suggest that there are important subtleties in the evolving cerebral injury that are not captured by the NIHSS composite score. Again, clinical scales are typically ordinal, not numerical, which argues against the presentation and interpretation of scales on a strict numerical basis as in the Mikulik et al study.25
So, is it possible that some component of the NIHSS examination, or the neurological examination in general, could be a more sensitive indicator of outcome?
| Back to the Future |
|---|
|
|
|---|
The basic principles, methods, and terminology used to evaluate scales for clinical research are well established. In addition, the use of composite scores for neurological assessment is pervasive. For example, in multiple sclerosis, one rating method converted the neurological examination into a weighted ordinal impairment scale.28 The various items making up the impairment scale were not expected to be homogeneous, so it was not at all surprising that various components of the scale appeared more responsive than the overall summary measure and others appeared less responsive to a treatment.29 So, one could postulate that in the stroke study reported by Mikulik and colleagues, certain components of the neurological examination might well be more sensitive to arterial recanalization than the summary NIHSS score and that other components are less sensitive.
This appears to be the case. In the prospective 2-chain rt-PA dose-finding study, 93 (of 104) patients with symptomatic documented cerebral arterial occlusions completed the intravenous rt-PA infusion within 5.4±1.7 hours after symptom onset.3 Each patient was scored by the same neurologist at baseline; 24, 48, and 72 hours; and subsequently, according to the unweighted neurological examination based on the Harvard Stroke Registry. After rt-PA infusion, 4 patients achieved complete recanalization, 31 had partial recanalization, and 58 experienced no recanalization by angiography at the completion of the rt-PA infusion.3
The neurological examination was divided into 4 subcategories: (1) general characteristics, including neurological status, consciousness, behavior, visual fields, eye movements, weakness, and sensory; (2) behavioral examination, consisting of hemineglect, language, nondominant syndrome, and memory disturbance; (3) sensory examination, consisting of face, shoulder, hand, hip, foot, and trunk evaluations; and (4) motor examination, consisting of tongue, face, shoulder, hand, hip, and foot evaluations. We found no significant difference between the complete/partial recanalization (35 patients) and no recanalization (58 patients) groups for each of the categories, with the exception of the sensory examination. To examine this difference further, the proportions of patients with abnormal findings for the hand and face sensation components of the sensory examination at each time point were observed (the Figure). Patients who achieved complete or partial recanalization improved dramatically over the first 24 hours compared with those patients without recanalization. Thereafter, the sensory responses seemed stable within each group. In that particular trial, then, sensation seemed to be an early (24 hour) indicator of recanalization status, more so than the other components of the neurological examination. Such fine distinctions may well be obscured in a summary measure, particularly if little weight is accorded the sensation domain in the summary. It is clear that, in that trial, severity of stroke at baseline as judged by neurological examination was related to recanalization outcome.
|
| Summary |
|---|
|
|
|---|
Indeed, predictive algorithms for stroke outcome based on baseline stroke severity and other well-known risk factors such as age and gender can be quite useful. In general, one might expect that clinical changes associated with recanalization would be greatest in the first 24 hours after stroke onset (especially if rt-PA is given within 3 hours of onset). Hence, a plausible scenario is that the recanalization group improves and the no-recanalization group does not in the first 24 hours, and the differences are then maintained over the next 2 days. Although the data tend to support this notion, we caution that only a few patients achieve complete recanalization with intravenous infusion of rt-PA, and combining patients with complete and partial recanalization outcomes may dilute the real effects of improved blood flow. More to the point, one might question the underlying premise that recanalization of a major artery should be associated with improved brain function. None of these studies has assessed the status of the collateral circulations, for instance.
In the end, it would be useful to know which elements of the scale(s) are most sensitive to recanalization. That indeed would add something new to the soup.
| Acknowledgments |
|---|
None.
| Footnotes |
|---|
| References |
|---|
|
|
|---|
2. del Zoppo GJ, Ferbert A, Otis S, Brückmann H, Hacke W, Zyroff J, Harker LA, Zeumer H. Local intra-arterial fibrinolytic therapy in acute carotid territory stroke: a pilot study. Stroke. 1988; 19: 307313.
3. del Zoppo GJ, Poeck K, Pessin MS, Wolpert SM, Furlan AJ, Ferbert A, Alberts MJ, Zivin JA, Wechsler L, Busse O, Greenlee R Jr, Brass L, Mohr JP, Feldmann E, Hacke W, Kase CS, Biller J, Gress D, Otis SM. Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol. 1992; 32: 7886.[CrossRef][Medline] [Order article via Infotrieve]
4. Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K, Tsutsumi A, Yamadori A. Intravenous recombinant tissue plasminogen activator in acute carotid artery territory stroke. Neurology. 1992; 42: 976982.
5. Yamaguchi T, Hayakawa T, Kikuchi H. Intravenous tissue plasminogen activator ameliorates the outcome of hyperacute embolic stroke. Cerebrovasc Dis. 1993; 3: 269272.[CrossRef]
6. Mohr JP, Caplan LR, Melski JW, Goldstein RJ, Duncan GW, Kistler JP, Pessin MS, Bleich HL. The Harvard Cooperative Stroke Registry: a prospective registry of patients hospitalized with stroke. Neurology. 1978; 28: 754762.
7. Mikulik R, Ribo M, Hill MD, Grotta JC, Malkoff M, Molina C, Rubiera M, Delgado-Mederos R, Alvarez-Sabin J, Alexandrov AV; for the CLOTBUST Investigators. Accuracy of serial National Institutes of Health Stroke Scale scores to identify artery status in acute ischemic stroke. Circulation. 2007; 115: 26602665.
8. Alexandrov AV, Demchuk AM, Burgin WS, Robinson DJ, Grotta JC, for the CLOTBUST Investigators. Ultrasound-enhanced thrombolysis for acute ischemic stroke: phase I: findings of the CLOTBUST trial. J Neuroimaging. 2004; 14: 113117.[CrossRef][Medline] [Order article via Infotrieve]
9. Alexandrov AV, Wojner AW, Grotta JC, for the CLOTBUST Investigators. CLOTBUST: design of a randomized trial of ultrasound-enhanced thrombolysis for acute ischemic stroke. J Neuroimaging. 2004; 14: 108112.[CrossRef][Medline] [Order article via Infotrieve]
10. Zanette EM, Fieschi C, Bozzao L, Roberti C, Toni D, Argentino C, Lenzi GL. Comparison of cerebral angiography and transcranial Doppler sonography in acute stroke. Stroke. 1989; 20: 899903.
11. Camerlingo M, Casto L, Censori B, Ferraro B, Gazzaniga GC, Mamoli A. Transcranial Doppler in acute ischemic stroke of the middle cerebral artery territories. Acta Neurol Scand. 1993; 88: 108111.[Medline] [Order article via Infotrieve]
12. Fieschi C, Argentino C, Lenzi GL, Sacchetti ML, Toni D, Bozzao L. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci. 1989; 91: 311321.[CrossRef][Medline] [Order article via Infotrieve]
13. Baumgartner RW, Mattle HP, Schroth G. Assessment of
50% and <50% intracranial stenoses by transcranial color-coded duplex sonography. Stroke. 1999; 30: 8792.
14. Demchuk AM, Christou I, Wein TH, Felberg RA, Malkoff M, Grotta JC, Alexandrov AV. Accuracy and criteria for localizing arterial occlusion with transcranial Doppler. J Neuroimaging. 2000; 10: 112.[Medline] [Order article via Infotrieve]
15. Christou I, Felberg RA, Demchuk AM, Burgin WS, Malkoff M, Grotta JC, Alexandrov AV. Intravenous tissue plasminogen activator and flow improvement in acute ischemic stroke patients with internal carotid artery occlusion. J Neuroimaging. 2002; 12: 119123.[Medline] [Order article via Infotrieve]
16. Burgin WS, Malkoff M, Felberg RA, Demchuk AM, Christou I, Grotta JC, Alexandrov AV. Transcranial Doppler ultrasound criteria for recanalization after thrombolysis for middle cerebral artery stroke. Stroke. 2000; 31: 11281132.
17. Saqqur M, Shuaib A, Alexandrov AV, Hill MD, Calleja S, Tomsick T, Broderick J, Demchuk AM. Derivation of transcranial Doppler criteria for rescue intra-arterial thrombolysis: multicenter experience from the Interventional Management of Stroke study. Stroke. 2005; 36: 865868.
18. Alexandrov AV, Sloan MA, Wong LK, Douville C, Razumovsky AY, Koroshetz WJ, Kaps M, Tegeler CH. Practice standards for transcranial Doppler ultrasound: part I: test performance. J Neuroimaging. 2007; 17: 1118.[Medline] [Order article via Infotrieve]
19. De Haan R, Horn J, Limburg M, Van Der Meulen J, Bossuyt P. A comparison of five stroke scales with measures of disability, handicap, and quality of life. Stroke. 1993; 24: 11781181.
20. Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH stroke scale. Stroke. 1994; 25: 362365.[Abstract]
21. Adams HPJ, Davis PH, Leira EC, Chang BH, Bendixen WR, Clarke RF, Woolson, Hansen MD. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: a report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Neurology. 1999; 53: 126131.
22. Kwiatkowski TG, Libman RB, Frankel M, Tilley BC, Morgenstern LB, Lu M, Broderick JP, Lewandowski CA, Marler JR, Levine SR, Brott T. Effects of tissue plasminogen activator for acute ischemic stroke at one year: National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. N Engl J Med. 1999; 340: 17811787.
23. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von KR, Boysen G, Bluhmki E, Hoxter G, Mahagne MH. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995; 274: 10171025.
24. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P, for the Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998; 352: 12451251.[CrossRef][Medline] [Order article via Infotrieve]
25. Koziol JA, Feng AC. On the analysis and interpretation of outcome measures in stroke clinical trials: lessons from the SAINT I study of NXY-059 for acute ischemic stroke. Stroke. 2006; 37: 26442647.
26. Koziol JA, Hacke W. Multivariate data reduction by principal components, with application to neurological scoring instruments. J Neurol. 1990; 237: 461464.[CrossRef][Medline] [Order article via Infotrieve]
27. Koziol JA, Frutos A, Sipe JC, Romine JS, Beutler E. A comparison of two neurologic scoring instruments for multiple sclerosis. J Neurol. 1996; 243: 209213.[CrossRef][Medline] [Order article via Infotrieve]
28. Sipe JC, Knobler RL, Braheny SL, Rice GP, Panitch HS, Oldstone MB. A neurologic rating scale (NRS) for use in multiple sclerosis. Neurology. 1984; 34: 13681372.
29. Koziol JA, Lucero A, Sipe JC, Romine JS, Beutler E. Responsiveness of the Scripps neurologic rating scale during a multiple sclerosis clinical trial. Can J Neurol Sci. 1999; 26: 283289.[Medline] [Order article via Infotrieve]
Related Article:
Circulation 2007 115: 2591.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2007 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |