This Article Abstract Full Text (PDF) All Versions of this Article: 35/5/1135    most recent 01.STR.0000125862.55804.29v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnold, M. Articles by Mattle, H. Search for Related Content PubMed PubMed Citation Articles by Arnold, M. Articles by Mattle, H. Pubmed/NCBI databases Medline Plus Health Information Stroke Related Collections Thrombolysis Acute Stroke Syndromes Other arteriosclerosis Emergency treatment of Stroke Angiography

(Stroke. 2004;35:1135.)
© 2004 American Heart Association, Inc.

Original Contributions

Outcome of Acute Stroke Patients Without Visible Occlusion on Early Arteriography

Marcel Arnold, MD; Krassen Nedeltchev, MD; Caspar Brekenfeld, MD; Urs Fischer, MD; Luca Remonda, MD; Gerhard Schroth, MD Heinrich Mattle, MD

From Departments of Neurology (M.A., K.N., U.F., H.M.) and Neuroradiology (C.B., L.R., G.S.), University of Bern, Bern, Switzerland.

Correspondence to Dr Heinrich Mattle, Department of Neurology, University of Berne, Freiburgstrasse, Inselspital, CH-3010 Berne, Switzerland. E-mail heinrich.mattle{at}insel.ch

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background— The aim of this study was to determine the clinical and radiological outcome of acute stroke patients who had no vessel occlusion on arteriography and to define predictors of clinical outcome.

Methods— We analyzed clinical and radiological data of stroke patients whose arteriography performed within 6 hours of symptom onset did not visualize any vessel occlusion.

Results— Twenty-eight of 283 consecutive patients (10%) who underwent arteriography with the intention to perform intraarterial thrombolysis did not show any arterial occlusion. Their median baseline National Institutes of Health Stroke Scale (NIHSS) score was 7. Time from symptom onset to arteriography ranged from 115 to 315 minutes; on average, it was 226 minutes. Presumed stroke cause was cardiac embolism in 11 patients (39%), small artery disease in 6 (21%), coronary angiography in 1 (4%), and undetermined in 10 patients (36%). After 3 months, modified Rankin Scale score (mRS) was 2 in 21 patients (75%), indicating a favorable outcome. Six patients (21%) had a poor outcome (mRS 3 or 4) and 1 patient (4%) had a myocardial infarction and died. Twenty-seven patients had follow-up brain imaging. It was normal in 5, showed a lacunar lesion in 8, a striatocapsular infarct in 2, a small or medium-sized anterior circulation infarct in 6, multiple small anterior circulation infarcts in 2, and multiple posterior circulation infarcts in 4. No predictors of clinical outcome were identified.

Conclusions— Most acute stroke patients with normal early arteriography show infarcts on brain imaging; however, clinical outcome is usually favorable.

Key Words: stroke • outcome • thrombolysis

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Asubgroup analysis of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial showed that patients with all stroke subtypes derived a clinical benefit from thrombolytic treatment.¹ Even in patients who were classified as having small vessel disease according to the Trial of Org 10172 in Acute Treatment (TOAST) criteria, thrombolysis improved the outcome. However, the demonstration of an arterial occlusion was not mandatory in NINDS. Therefore, the question whether acute stroke patients without arterial occlusion should be treated with thrombolysis has not been resolved yet.^2,3 The answer depends mainly on the spontaneous course of such patients. For this reason, we analyzed our acute stroke patients who underwent arteriography with the intention to perform intraarterial thrombolysis (IAT) but who did not show any occluded vessel and therefore were not treated. The aim was to determine their clinical and radiological outcome and to identify predictors of clinical outcome.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
From January 1998 to December 2002, 283 patients with acute cerebral ischemia met our institutional criteria for IAT and therefore underwent cerebral arteriography immediately after clinical evaluation and computerized tomography (CT) or magnetic resonance imaging (MRI). The indications for IAT have been published previously.⁴ Eventually, 191 patients with occlusions of intracranial vessels correlating to the clinical signs underwent IAT. In 92 (33%) patients, IAT was not performed for the following reasons: occlusion of small branches only of the middle cerebral artery (MCA) or the posterior cerebral artery (n=7 or n=1, respectively); extracranial carotid artery occlusion or high-grade stenosis (n=49) or vertebral artery occlusion and contralateral vertebral hypoplasia (n=5) preventing access to the occluded intracranial artery; aortic dissection (n=2); and no visualization of any occlusion of an intracranial artery (n=28). Data of the latter 28 patients without intracranial vessel occlusion were analyzed and are the subject of this study. The neurological status was assessed after admission using the NIHSS score by a neurologist.⁵ The clinical stroke subtypes were categorized according to the Oxfordshire Community Stroke Project (OCSP) classification.⁶ All patients immediately underwent CT or MR scans after neurological evaluation to exclude intracerebral hemorrhage. Early parenchymal CT signs of ischemia were defined according to the criteria by von Kummer et al.⁷ Arteriography was performed by transfemoral approach. All patients received a 4-vessel diagnostic arteriography to assess the complete vessel status and collateral circulation if present. Either a control CT (n=3) or control MRI (n=26) scan was performed 1 or 2 days after arteriography. CT or MRI lesions were classified similar to the criteria published by Mead et al⁸ as follows: (1) large cortical MCA infarct (more than half of the MCA territory); (2) medium-sized or small anterior circulation infarct (less than half or the MCA territory or any of the ACA territory); (3) large (>1.5 cm) subcortical infarct (striatocapsular); (4) lacunar (<1.5 cm) anterior circulation infarct; (5) lacunar (<1.5 cm) posterior circulation infarct; and (6) nonlacunar posterior circulation infarct.

Stroke cause was determined using additional investigations as necessary and classified according to the TOAST criteria.⁹ Outcome was assessed 3 months after the ictus by clinical examination using the modified Rankin scale (mRS).¹⁰ The mRS scale scores of 0 to 2 were defined as "favorable" and mRS scores of 3 to 5 as "poor" outcome. Death corresponds to a mRS score of 6. For the analysis of predictors of clinical outcome, we considered variables that may influence clinical outcome and dichotomized patients into 2 groups (patients with favorable outcome [mRS 2] versus patients with poor outcome or death [mRS 3 to 6]).

Statistical analysis was performed with SPSS 10 statistical software (SPSS Inc). Comparisons of clinical and radiological characteristics and outcome were performed using Fisher exact test. Two-sided P<0.05 were considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Demographic, Clinical, and Radiological Data
Twenty-eight patients (21 men, 7 women) with a mean age of 58±12 (range 18 to 82) years who did not show any vessel occlusion on early arteriography were identified. The median baseline NIHSS on admission was 7 and ranged from 4 to 25. Clinical neurological examinations indicated a lacunar syndrome in 7 patients (25%), a partial anterior circulation syndrome in 15 (54%), and a posterior circulation syndrome in 6 patients (21%). No total anterior circulation syndrome was observed. The mean time from symptom onset to arteriography was 226 minutes (range 115 to 325 minutes). All but 1 admission CT was normal. Only 1 patient (4%) showed early parenchymal CT signs of ischemia, and other abnormalities such as hyperdense artery signs were not observed. Presumed stroke cause was cardiac embolism in 11 patients (39%), small artery disease in 6 (21%), iatrogenic after coronary angiography in 1 (4%), and undetermined in 10 patients (36%).

Radiological Outcome
On follow-up brain imaging, 8 patients (29%) showed a lacunar lesion, 2 (7%) had a striatocapsular infarct, 6 (21%) had a small- or medium-sized anterior circulation infarct, 2 (7%) had multiple anterior circulation infarcts, and 4 (14%) had multiple posterior circulation infarcts. In 5 patients (18%), follow-up MRI (n=4) or CT (n=1) did not reveal any ischemic lesion. One patient (4%) with rapid resolution of his clinical deficits had clinical but no imaging follow-up. Baseline data and clinical and radiological outcome of each patient are summarized in Table 1.

View this table: [in this window] [in a new window]   TABLE 1. Baseline Data and Clinical and Radiological Outcome of Each Patient

Clinical Outcome
After 3 months, mRS was 2 in 21 patients (75%), indicating a favorable outcome. Six patients (21%) had a poor outcome (mRS 3 or 4). One patient (4%) had a myocardial infarction 1 day after his stroke and died. Before myocardial infarction, his NIHSS score was 8.

Predictors of Outcome
Age, sex, initial NIHSS score, clinical stroke syndrome, time to arteriography, stroke cause, early signs of ischemia on admission CT, and vascular risk factors failed to predict clinical outcome (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Predictors of Clinical and Radiological Outcome

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The outcome of 28 acute stroke patients with normal early arteriograms was favorable in 21 (75%). This is the main message of our study. Nevertheless, the majority (78%) has cerebral infarction according to brain imaging, and death or significant disability occurs in one quarter of the patients. Another small series of 10 patients without a visible clot on arteriography that was performed within 4 hours of symptom onset gave similar results. Eight of 10 follow-up brain scans showed a new cerebral infarct.¹¹ Four of these 10 patients (40%) were disabled (mRS>2) after 3 months. Good outcomes were also reported in 4 of 5 patients of another series who had been treated with IAT, even without visible occlusion on arteriography.¹²

There may be 2 pathomechanisms leading to ischemic stroke and disability in patients with normal arteriography. First, occlusions of arterioles are not visualized on clinical arteriography. They may account for most of the lacunar infarcts. Second, an occlusion of a larger vessel may cause an ischemic stroke before it recanalizes spontaneously. Such a mechanism may be operative when collaterals are inadequate to preserve perfusion until recanalization occurs.

The question arises whether it is justified to exclude patients without occlusion on arteriography from thrombolytic therapy. To date, the answer cannot be derived from randomized trials or controlled studies. In the present series, little may have been gained with thrombolysis. The majority had a favorable clinical outcome without treatment. The question that remains is the one of arteriolar occlusions, ie, whether such patients have a salvageable penumbra. The answer cannot be given from our angiography series, because neither CT nor any clinical findings was predictive of the outcome. The shortcoming of our study is that we did not perform systematically perfusion CT or perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) MRI before arteriography. These techniques might have been helpful to identify potential candidates for thrombolysis despite normal arteriography. Schellinger et al evaluated DWI and PWI and magnetic resonance angiography (MRA) within 6 hours of stroke onset.¹³ Of 8 patients with normal intracranial MRA, 4 had small lacunar, 2 basal ganglia, and 2 presumedly cardioembolic infarcts. A small PWI–DWI mismatch indicating salvageable tissue was observed in only 1 of the 8 patients. Based on pathophysiological considerations, the authors recommended no thrombolysis in patients without vessel occlusion and without PWI–DWI mismatch. They would, however, reluctantly and carefully perform thrombolysis in patients with PWI–DWI mismatch but no vessel occlusion. However, DWI-positive patients may show imaging lesion reversal.¹⁴ Therefore, these recommendations, which are based on pathophysiological considerations, have to be confirmed by randomized controlled trials.

In conclusion, acute stroke patients with normal arteriograms will mostly have a favorable spontaneous recovery. The chances to prevent the few unfavorable outcomes in such patients with thrombolysis may be small, because the ischemic damage is probably irreversibly set already at the time of arteriography. This statement is based on pathophysiological considerations. In the intravenous NINDS trial, a clinical benefit was shown in all subgroups of patients, including patients with small artery disease. However, vessel imaging was not mandatory in the NINDS study. Hopefully, ongoing clinical studies based on DWI and PWI or vessel imaging or both (eg, EPITHET, DIAS, SaTIS, DEFUSE) will improve patient selection and give the answer whether stroke patients with normal vessel status will benefit from thrombolysis.¹⁵

	Acknowledgments

 
We thank Dr Pietro Ballinari for statistical advice.

Received November 11, 2003; revision received January 7, 2004; accepted January 23, 2004.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. The NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke. Subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. 1997; 28: 2119–2125.[Abstract/Free Full Text]
2. Caplan LR, Mohr JP, Kistler JP, Koroshetz W. Should thrombolytic therapy be the first-line treatment for acute ischemic stroke? Thrombolysis—not a panacea for ischemic stroke. N Engl J Med. 1997; 337: 1309–1310.[Free Full Text]
3. Caplan LR. Treatment of patients with stroke. Arch Neurol. 2002; 59: 703–707.[Free Full Text]
4. Arnold M, Schroth G, Nedeltchev K, Loher T, Remonda L, Stepper F, Sturzenegger M, Mattle HP. Intraarterial thrombolysis in 100 patients with acute stroke due to middle cerebral artery occlusion. Stroke. 2002; 33: 1828–1833.[Abstract/Free Full Text]
5. Brott T, Adams HP Jr, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V, Roorick M, Moomaw CJ, Walker M. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989; 20: 864–870.[Abstract/Free Full Text]
6. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet. 1991; 22: 337:1521–1526.
7. von Kummer R, Allen KL, Holle R, Bozzao L, Bastianello S, Manelfe C, Bluhmki E, Ringleb P, Meier DH, Hacke W. Acute stroke: usefulness of early CT findings before thrombolytic therapy. Radiology. 1997; 205: 327–333.[Abstract/Free Full Text]
8. Mead GE, Lewis SC, Wardlaw JM, Dennis MS, Warlow CP. How well does the Oxfordshire community stroke project classification predict the site and size of the infarct on brain imaging? J Neurol Neurosurg Psychiatry. 2000; 68: 558–562.[Abstract/Free Full Text]
9. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE III. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24: 35–41.[Abstract/Free Full Text]
10. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988; 19: 604–607.[Abstract/Free Full Text]
11. Derex L, Tomsick TA, Brott TG, Lewandowski CA, Frankel MR, Clark W, Starkman S, Spilker J, Udsten GJ, Khoury J, Grotta JC, Broderick JP; EMS Bridging Trial. Outcome of stroke patients without angiographically revealed arterial occlusion within four hours of symptom onset. AJNR Am J Neuroradiol. 2001; 22: 685–690.[Abstract/Free Full Text]
12. Schumacher M, Yin L, Klisch J, Hetzel A. Local intraarterial fibrinolysis without arterial occlusion? Neuroradiology. 1999; 41: 530–536.[CrossRef][Medline] [Order article via Infotrieve]
13. Schellinger PD, Fiebach JB, Jansen O, Ringleb PA, Mohr A, Steiner T, Heiland S, Schwab S, Pohlers O, Ryssel H, Orakcioglu B, Sartor K, Hacke W. Stroke magnetic resonance imaging within 6 hours after onset of hyperacute cerebral ischemia. Ann Neurol. 2001; 49: 460–469.[CrossRef][Medline] [Order article via Infotrieve]
14. Kidwell CS, Alger JR, Saver JL. Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke. 2003; 34: 2729–2735.[Abstract/Free Full Text]
15. Major ongoing stroke trials. Stroke. 2003; 34: e61–e72.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				L. R. Caplan Stroke Thrombolysis: Slow Progress Circulation, July 18, 2006; 114(3): 187 - 190. [Full Text] [PDF]

				U. Fischer, M. Arnold, K. Nedeltchev, C. Brekenfeld, P. Ballinari, L. Remonda, G. Schroth, and H. P. Mattle NIHSS Score and Arteriographic Findings in Acute Ischemic Stroke Stroke, October 1, 2005; 36(10): 2121 - 2125. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 35/5/1135    most recent 01.STR.0000125862.55804.29v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arnold, M. Articles by Mattle, H. Search for Related Content PubMed PubMed Citation Articles by Arnold, M. Articles by Mattle, H. Pubmed/NCBI databases Medline Plus Health Information Stroke Related Collections Thrombolysis Acute Stroke Syndromes Other arteriosclerosis Emergency treatment of Stroke Angiography