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(Stroke. 2002;33:1828.)
© 2002 American Heart Association, Inc.

Original Contributions

Intra-Arterial Thrombolysis in 100 Patients With Acute Stroke Due to Middle Cerebral Artery Occlusion

Marcel Arnold, MD; Gerhard Schroth, MD; Krassen Nedeltchev, MD; Thomas Loher, MD; Luca Remonda, MD; Frank Stepper, MD; Matthias Sturzenegger, MD Heinrich P. Mattle, MD

From the Departments of Neurology (M.A., K.N., F.S., M.S., H.P.M.) and Neuroradiology (G.S., L.R.), Inselspital, University of Berne, Switzerland.

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

	Abstract

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Background and Purpose— The purpose of this study was to evaluate the safety and efficacy of local intra-arterial thrombolysis (LIT) using urokinase in patients with acute stroke due to middle cerebral artery (MCA) occlusion.

Methods— We analyzed clinical and radiological findings and functional outcome 3 months after LIT with urokinase of 100 consecutive patients. To measure outcome, the modified Rankin scale (mRs) score was used.

Results— Angiography showed occlusion of the M₁ segment of the MCA in 57 patients, of the M₂ segment in 21, and of the M₃ or M₄ segment in 22. The median National Institutes of Health Stroke Scale (NIHSS) score at admission was 14, and, on average, 236 minutes elapsed from symptom onset to LIT. Forty-seven patients (47%) had an excellent outcome (mRs score 0 to 1), 21 (21%) a good outcome (mRs score 2), and 22 (22%) a poor outcome (mRs score 3 to 5). Ten patients (10%) died. Excellent or good outcome (mRs score 2) was seen in 59% of patients with M₁ or M₂ and 95% of those with M₃ or M₄ MCA occlusions. Recanalization as seen on angiography was complete (thrombolysis in myocardial infarction [TIMI] grade 3) in 20% of patients and partial (TIMI grade 2) in 56% of patients. Age <60 years (P<0.05), low NIHSS score at admission (P<0.00001), and vessel recanalization (P=0.0004) were independently associated with excellent or good outcome and diabetes with poor outcome (P=0.002). Symptomatic cerebral hemorrhage occurred in 7 patients (7%).

Conclusions— LIT with urokinase that is administered by a single organized stroke team is safe and can be as efficacious as thrombolysis has been in large multicenter clinical trials.

Key Words: outcome • stroke, acute • thrombolytic therapy • urokinase

	Introduction

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Intravenous thrombolysis (IVT) using recombinant tissue plasminogen activator (rt-PA) has been shown to be an effective treatment for ischemic stroke within the first 3 hours after symptom onset.¹ Local intra-arterial thrombolysis (LIT) using recombinant prourokinase has also been found to improve outcome in patients with acute M₁ or M₂ segment occlusions of the middle cerebral artery (MCA), when administered within 6 hours.²

Several series showed that IVT or LIT can be safely and efficaciously applied in everyday practice.^3,4 However, especially for the intra-arterial approach, data from large, homogeneous, and nonrandomized patient series are still rare.⁵ Therefore we report our experience with 100 patients with MCA occlusions treated with LIT.

	Materials and Methods

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From December 1992 to November 2000, 100 consecutive patients (44 women and 56 men) with acute ischemic stroke due to MCA occlusions were treated with LIT using urokinase in our hospital. Twenty-three of these patients have been reported earlier.⁶ In the same period, 55 additional patients underwent angiography and LIT for treatment of acute stroke due to occlusion of other vessels. Twenty-four of them had posterior circulation, 26 carotid, and 5 anterior cerebral artery occlusions. From January 1998 to November 2000, 168 patients with acute ischemic stroke underwent angiography. One hundred seven (64%) received LIT, but in 61 patients LIT was not performed because of the following reasons: internal carotid (n=33) or vertebral artery occlusion and contralateral vertebral hypoplasia (n=2) preventing access to the occluded intracranial vessel, no visualization of any arterial occlusion explaining the neurological deficit (n=24), and aortic dissection (n=2). Before 1998 we did not record all angiographies routinely; only those with acute stroke and LIT were noted in a separate registry.

The neurological status was assessed at admission by a neurologist using the National Institutes of Health Stroke Scale (NIHSS).⁷ LIT was performed if (1) clinical diagnosis of ischemic stroke was established by a neurologist; (2) baseline NIHSS score reached at least 4 points, except for isolated hemianopia or aphasia; (3) CT (n=97) or MRI (n=3) excluded intracranial hemorrhage; (4) 4-vessel cerebral angiography showed a vessel occlusion correlating to the neurological deficit; (5) the expected interval from symptom onset to LIT was <6 hours; (6) there were no individual clinical or laboratory findings advising against thrombolysis; and (7) for patients >75 years of age, their general condition before stroke was not advising against it. IVT was performed within a 3-hour time window, when intra-arterial delivery of the thrombolytic agent into the MCA was not possible because of occlusion of the ipsilateral extracranial internal carotid artery (n=6). Early signs of ischemia on CT were analyzed according to the criteria described by von Kummer et al.⁸ For MRI we routinely used fast spin echo and gradient echo sequences.⁹ Regarding risk factors, diabetes mellitus refers to a past history of diabetes and hypertension to a history of hypertension.

Selective intra-arterial digital subtraction angiography was performed on a biplane, high-resolution angiography system (Toshiba CAS 500) with a matrix of 1024x1024 pixels. A 5.5 F-JB2 catheter (Valavanis) was inserted into the femoral artery and guided to the cerebral arteries for diagnostic 4-vessel angiography. All 100 patients were treated by LIT using a microcatheter, mostly a Fast Tracker 18 (Target Therapeutics) through the 5.5-F JB2 catheter, which was navigated into the occluded MCA. Urokinase (Urokinase HS Medac) in a mean dose of 863 000 IU (range 20 000 to 1 250 000 IU) was infused directly into or near the proximal end of the occluding thrombus over 60 to 90 minutes in M₁ or M₂ occlusions. In patients with M₃/M₄ occlusion urokinase was infused as close to the clot as possible, mostly in the M₂ segment. In 8 patients with M₁ or M₂ occlusion due to soft thrombotic material, mechanical disruption of the clot was performed in addition using a very flexible hydrophilic guidewire catheter (Silver Speed MTI 0.008 or 0.010 inch). The tip of the guidewire was formed in a J shape to avoid perforation of the vessel walls. Penetration and fragmentation of the thrombus was achieved by gently advancing and rotating the convex border of the J-shaped guidewire. In 2 patients without recanalization after injection of 1 000 000-IU urokinase a percutaneous transluminal angioplasty was performed using a FasStealth balloon dilatation catheter (Target Therapeutics) with a balloon diameter of 2.00 mm. Treatment effect was documented by control angiography immediately after administration of urokinase. Eighteen patients who had been treated before publication of the International Stroke Trial results received heparin in a dose doubling the activated thromboplastin time immediately after LIT.¹⁰ After the International Stroke Trial results were published, 250 to 500 mg aspirin was given to all patients (n=82) instead of heparin.

All of the angiograms were analyzed by a neuroradiologist. Recanalization was assessed on the control angiogram after LIT and classified according to thrombolysis in myocardial infarction (TIMI) grades,¹¹ as follows: no recanalization, TIMI grade 0; minimal recanalization, TIMI grade 1; partial recanalization, TIMI grade 2; and complete recanalization, TIMI grade 3. Collaterals were classified into the following 2 groups: poor, if none or minimal leptomeningeal anastomoses were visualized and no or minimal filling of the occluded vessel territory was seen, and good, if leptomeningeal anastomoses filled the occluded vessel territory by more than half. Classification of collaterals was possible in 98 of 100 patients. In 2 patients the digitally stored data were lost and documentation of the angiograms on films did not allow classifying the collaterals. Control CT scan or MRI was routinely performed within the first 24 hours after thrombolysis. Additional subsequent CT scans were performed in all patients with neurological deterioration. A symptomatic intracerebral hemorrhage (ICH) was defined as a homogeneous area of hemorrhage with clinical neurological deterioration.²

We assessed infarct etiology with additional investigations if necessary and classified each patient according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.¹² Outcome was assessed by different neurologists with a clinical examination 3 months after LIT using the modified Rankin scale (mRs).¹³ mRs scores of 0 or 1 were defined as excellent outcome, 2 as good, and 3 to 5 as poor. Death corresponds to mRs score of 6. The investigators were not blinded to the baseline scores and angiographic results.

Statistical analysis was performed using SPSS 10 for MacIntosh statistical software (SPSS Inc, 2001). For comparison of outcome, we divided patients into 2 groups with either favorable or poor outcome, those with mRs score2 and those with mRs score 3 to 6. The ² test was used for cross-tabulation. Then, logistic regression analyses with a backward stepwise method were performed to determine the independent association of favorable outcome with other clinical and radiological factors. To determine predictors of recanalization, ² test was used. To determine differences between patients with and without ICHs, a Fisher exact test was applied. For analyzing the time variable, patients were dichotomized into those treated within 4 and >4 hours of symptom onset. A probability value of P<0.05 was considered significant.

	Results

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Demographic, Clinical, and Radiological Data
The mean age of the patients was 61 years (range, 19 to 83 years). The median NIHSS score at admission was 14 and ranged from 3 to 24. The mean delay (±1 SD) from symptom onset of cerebral ischemia to thrombolysis was 236±74 minutes. Baseline CT scans showed early signs of ischemia in 41 of 97 patients (42%). In all 3 patients without CT scans, diffusion-weighted MRI showed signal abnormalities in the MCA territory. Thirty-six patients (38%) showed a dense artery sign on their initial CT scan. Angiography visualized occlusion of the M₁ segment of the MCA in 57 patients, of the M₂ segment of the MCA in 21 patients, and of the M₃ or M₄ segments of the MCA in 22 patients.

Stroke etiology was cardioembolic in 62 patients. Large-artery atherosclerosis was present in 14, stroke of other determined etiology in 7, and stroke of undetermined etiology in 17 patients. Thirteen patients had a history of a previous cerebrovascular event. Nineteen patients were diabetics, 49 had hypertension, 34 had hypercholesterolemia, and 25 were current smokers.

In patients with M₁ (n=57) or M₂ (n=21) occlusions, mean age was 59 years. The mean delay from symptom onset to therapy was 234 minutes; the median NIHSS score at admission was 14 (range 4 to 24). In patients with M₃ or M₄ occlusions (n=22), mean age was 66 years. The mean interval from symptoms to therapy was 245 minutes; the median NIHSS score at admission was 10 (range 3 to 17).

Outcome
Three months after the stroke 47 patients (47%) had recovered to mRs score 0 or 1 (excellent outcome) and 21 patients (21%) to mRs score 2 (good outcome). The outcome was poor (mRs score 3 to 5) in 22 patients (22%). Mortality was 10% (10 patients).

Among the 78 patients with M₁ or M₂ occlusions, 33 (42%) had an excellent outcome at 3 months, 13 (17%) a good outcome, and 22 (28%) a poor outcome. Mortality was 13% (10 patients).

In the group with M₃ or M₄ occlusions (n=22), the percentage of patients with excellent outcome was 63% (14 patients), good outcome 32% (7 patients), and poor outcome 5% (1 patient). No patient died (Figure).

View larger version (14K): [in this window] [in a new window]   mRs score at 3 months according to occluded vessel segments of the MCA.

Predictors of Clinical Outcome
Logistic regression analyses showed the following independent predictors of favorable outcome: age <60 years (P=0.04), low NIHSS score at admission (P<0.00001), and vessel recanalization (P=0.0004).

Diabetes mellitus was associated with a poor outcome (P=0.002). There was no association between outcome and sex, hypertension, smoking, stroke etiology, early CT signs, hyperdense MCA sign (HMCAS) on CT scan, time interval to treatment, or good or poor collaterals (Table 1).

View this table: [in this window] [in a new window]   Table 1. Independent Predictors of Clinical Outcome at 3 Months

Recanalization
Complete recanalization (TIMI grade 3) was achieved in 20 patients (20%) and partial recanalization (TIMI grade 2) in 56 patients (56%). This corresponds to a partial or complete recanalization rate of 76%. In patients with M₁ or M₂ occlusions, the rate of complete or partial recanalization was 79% (62 of 78 patients) and in patients with M₃ or M₄ occlusions 64% (14 of 22 patients). The TIMI recanalization rates are shown in Table 2.

View this table: [in this window] [in a new window]   Table 2. TIMI Recanalization Grades According to the Occluded Segments of the MCA

Four of the 8 patients with M₁ or M₂ occlusion and mechanical disruption of the thrombus showed complete recanalization and 2 showed partial recanalization, with a good outcome in 3, poor outcome in 3, and death in 2 patients. Twice PTA of the MCA was performed with complete recanalization and good outcome in 1 patient and partial recanalization and death in the other.

There was no association between recanalization and age, baseline NIHSS score, time to treatment, HMCAS, early signs of ischemia on CT scan, or stroke etiology. However, there was a trend toward a better recanalization in patients with good collaterals (Table 3).

View this table: [in this window] [in a new window]   Table 3. Predictors of Vessel Recanalization

Hemorrhages
Symptomatic ICH occurred in 7 patients (7%), 4 within 24 hours after treatment, 1 on day 2, and 2 on day 3 after thrombolysis. All ICHs occurred in patients with M₁ (4 of 57 patients) or M₂ occlusions (3 of 21 patients), which resulted in a hemorrhage rate of 9% (7 of 78 patients) for patients with M₁ or M₂ occlusions and of 0% for patients with M₃ or M₄ occlusions. Two of the 7 patients with ICHs died, 3 had a poor outcome, 1 a good outcome, and 1 an excellent outcome.

There was no association between symptomatic ICH and hypertension, hypercholesterolemia, diabetes, baseline NIHSS score, time to treatment, early CT signs, good or poor recanalization, or good or poor collaterals (Table 4).

View this table: [in this window] [in a new window]   Table 4. Predictors of Symptomatic Cerebral Hemorrhage

Extracranial bleedings occurred in 3 patients (3%), in 2 at the puncture site of the catheter and in 1 patient from the gastrointestinal tract. None of the extracranial hemorrhages was life threatening, and none needed transfusion or surgical intervention.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Outcome and Comparison With Randomized Trials
Intra-arterial thrombolysis has been shown to be effective for treatment of patients with acute stroke due to occlusion of the M₁ or M₂ segment of the MCA.² However, there is always concern that under routine clinical conditions therapeutic intervention may have higher risks and be less effective than under trial conditions.

Our results with 59% excellent or good outcomes (mRs score 2) in patients with M₁ or M₂ occlusions and 96% excellent or good outcomes in patients with M₃ or M₄ occlusions indicate that LIT using urokinase can be safe and efficacious when applied by a well-organized stroke team. The proportion of our patients with M₁ or M₂ occlusions who regained functional independence was even higher than in the Prolyse in Acute Cerebral Thromboembolism (PROACT) II study (59% versus 40%), and mortality was lower (13% versus 25%).²

These differences might be explained by the lower median baseline NIHSS score of our patients compared with the PROACT II patients (14 versus 17). In addition, the younger age (59 versus 64 years) and the lower median time to treatment (3.9 hours versus 5.3 hours) favored our patients.

Differences in patient selection, vessel territories involved, and stroke subtypes limit a comparison with the NINDS trial using intravenous rt-PA. The percentage of our patients with minimal or no disability (mRs score 1) was higher than in the NINDS study (47% versus 42%) despite earlier treatment (within 3 hours of symptom onset) in NINDS and an identical median baseline NIHSS score of 14 in both studies. In addition, the mortality of 10% at 3 months in our patients was lower than that of the NINDS trial (17%). In a recent small subgroup analysis from an IVT open-label study, only 30% of 20 patients with M₁ occlusions diagnosed by transcranial Doppler ultrasound recovered to mRs score 0 to 2, indicating that IVT is probably less effective than LIT when the MCA main stem is occluded.¹⁴

In the patients with M₃ or M₄ occlusions, only 1 of 22 patients (5%) had a poor outcome and there were no deaths. The results are encouraging but do not allow a statement about efficacy in these patients because of the lack of a control group. It is probable that the good results are due to mild neurological deficits before LIT (median NIHSS score 10) and a spontaneous benign course in these patients.

Predictors of Outcome
In our series, patients younger than 60 years, with low baseline NIHSS score before thrombolysis, and with successful recanalization had a significantly better outcome than other patients. Each of these 3 factors was an independent predictor of favorable outcome. This is consistent with observations in NINDS and other patient series.^1,15,16

On the other hand, diabetes mellitus was an independent predictor of unfavorable outcome in our series. Jorgensen et al¹⁷ reported that high glucose concentration was an independent predictor of poor outcome in stroke patients. It has been shown that hyperglycemia is related to decreased cerebral blood flow and cerebrovascular reserve and to cellular acidosis in ischemic tissue.^18,19

The time from symptom onset to treatment did not exert an independent effect on the clinical outcome in our patients treated within 6 hours. It may indicate that some patients may have sufficient collaterals to preserve a large penumbra for a prolonged period of several hours. The missing correlation between the time to treatment and outcome also questions the current concept of a 6-hour therapeutic time window for intra-arterial thrombolysis. If the hypothesis of collaterals that preserve a large penumbra is true, a correlation between well-visualized collaterals on the arteriogram and outcome should be observed. There was only a nonsignificant trend that well-visualized collaterals on the arteriogram correlated with a better outcome. A potential explanation for this might be a methodological problem. In both the anteroposterior and the lateral view of the arteriogram, collaterals are always superimposed on normal arteries, which makes it difficult to assess the amount of functioning collaterals in the individual patient. MRI with perfusion- and diffusion-weighted imaging might help more to select patients with good collaterals who might benefit from LIT even after a long interval from onset of symptoms, eg, patients with a large volume of reduced perfusion and at the same time a small volume of abnormal diffusion.²⁰

There was no independent association between sex, hypertension, smoking, hypercholesterolemia, stroke etiology, early CT signs, HMCAS on CT scan or amount of collaterals, and outcome in our patients. There were nonsignificant trends toward better outcomes in men, patients without hypertension, patients treated within 4 hours, patients without HMCAS and without early signs of ischemia on CT scan, and patients with better collaterals. These results should be interpreted with caution and should not influence clinical decisions because of the small sample size.

Recanalization
The partial or complete recanalization rate was 76% for all MCA patients, 79% for patients with M₁ or M₂ occlusions, and 64% for those with M₃ or M₄ occlusions. These results are in the upper range of the rates of randomized trials^2,21 and other open LIT series with various agents and vascular territories,^4,15,22,23 in which recanalization rates from 58% to 100% were reported.

Partial or complete recanalization of 66% in PROACT II was lower than in this series with 79%. Mechanical disruption of the clot or PTA, in addition to pharmacological thrombolysis, was performed in 10 patients in this series, whereas this was not permitted in PROACT II.

A nonsignificant trend toward better recanalization in M₁/M₂ occlusions was observed compared with M₃/M₄ occlusions. Potential explanations are direct infusions of urokinase into the clot with M₁/M₂ occlusions, which was not possible in M₃/M₄ occlusions. In addition, mechanical disruption or PTA led to recanalization in 7 patients with M₁/M₂ occlusions. There may also be hemodynamic reasons. The blood flow pressure gradient in the MCA mainstem is higher than in the periphery, and therefore the force to dislodge the clot might be greater. It was not possible to identify predictors of recanalization, except for a nonsignificant trend toward better recanalization when sufficient collaterals were observed (Table 2). The missing association between recanalization and collaterals, baseline NIHSS score, time to treatment, HMCAS, and stroke etiology might be explained by the fact that the size of the thrombus or embolus and its composition might determine the likelihood of recanalization. Unfortunately, methods to assess these factors reliably in clinical medicine have yet to be created. Another explanation might be the small number of patients in our series.

Symptomatic ICH
Our rate of symptomatic ICH (7%) is on the same order of that of the NINDS cohort (6.4%) and other randomized intravenous rt-PA trials^24,25 and the intra-arterial PROACT II trial (10.2%).

If patients at high risk of cerebral bleeding can be identified and excluded from thrombolysis, then the safety and outcome from thrombolysis could be optimized. In this series we could not find any factors predicting ICH. This result may be due to the small sample size, because in the NINDS trial patients with a high baseline NIHSS score and those with clear edema or mass effect on early CT changes were at higher risk of bleeding than other patients.²⁶

Comparison of LIT and IVT
Direct comparisons of LIT and IVT have not been performed to date. Assessing the angiographic recanalization rates in MCA occlusions, del Zoppo et al²⁷ found 26% (12 of 46 vessels) complete or partial recanalizations after IVT for MCA main stem occlusion. Burgin et al²⁸ reported a 60% complete or partial angiographic recanalization rate after IVT in 25 patients with MCA occlusions. In PROACT 66% of MCAs have been recanalized, and in this series 79% of M₁ or M₂ occlusions have been recanalized. Because there is a correlation between recanalization and outcome, a cautious conclusion would be that the intra-arterial approach seems to be as effective as IVT when the main stem of the MCA is occluded. In peripheral occlusions (ie, M₃ and M₄ segments), such data allowing a comparison of IVT and LIT are lacking.

Limitations
Our study has some limitations. First, it is a retrospective review. Second, the follow-up examinations were not blinded Third, the study population might not be representative for the whole stroke population because of a referral bias that favors younger patients. Younger patients are more likely referred to a stroke center than older patients.

Conclusion
Our results indicate that LIT used by an organized stroke team in a routine clinical setting can be safe and efficacious in patients with M₁ or M₂ occlusions. It remains unclear whether the good results in M₃ or M₄ occlusions are due to thrombolysis or to a benign spontaneous course. Further research is needed to answer this question and to compare LIT with IVT or even a combined intra-arterial/intravenous approach.²⁹

	Acknowledgments

 
We thank Pietro Ballinari, PhD, for statistical advice.

Received November 20, 2001; revision received February 18, 2002; accepted April 10, 2002.

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