Thrombolysis with recombinant tissue plasminogen stroke: evalu

activ .ation

rator i with

n acute ischem rCBF-SPECT

HerderscheC D, Limburg M, van Royen EA, Hijdra A, Biiller HR, Koster PA. Thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke: evaluation with rCBF-SPECT. Acta Neurol Scand 1991: 83: 317-322.

We treated five patients with hemispheric ischemic stroke with intravenous recombinant tissue plasminogen activator (rtPA), within 3-6 h after stroke onset. Regional cerebral blood flow was evaluated with single photon emission computed tomography (rCBF-SPECT) before and after treatment. One patient with aphasia and a moderately severe hemiparesis, who had a small flow deficit, was treated 5 h and 30 min after the onset of his stroke and had a prompt and complete recovery. The post treatment rCBF-SPECT showed normal flow. One patient with a very large flow deficit died of transtentorial herniation. In three other patient clinical condition remained unchanged, in one of them despite restoration of flow, demonstrated by transcranial doppler examination. In all these patients the rCBF-SPECT remained abnormal. rCBF-SPECT is a valuable tool in the explanatory analysis of fibrinolytic treatment in ischemic stroke.

The pathogenetic mechanism in most cerebral in- farctions is arterial occlusion by an embolus or local thrombus. Recent case series show successfull clot lysis and clinical improvement with shortlasting local intra-arterial administration of urokinase or strep- tokinase, early after stroke onset (1,2). Intra- venously administered recombinant tissue plasmino- gen activator (rtPA) has been evaluated in myo- cardial infarction and might be superior to the con- ventional fibrinolytic agents with regard to both safety and efficacy (3).

The evaluation of such a treatment in stroke patients poses some special problems. Most ischemic strokes occur in the territory of the middle cerebral artery (MCA), which may be totally affected when the internal carotid artery or the MCA-stem is occluded. Such large lesions often lead to massive edema, with brain swelling and death. There is a remote possibility that early reperfusion promotes edema formation in such large lesions (4). Further- more, the extent of the lesion is an important deter- minant for the risk of hemorrhage, when anticoagu- lants are used (5 ) . MCA-branch occlusions lead to smaller cortical infarcts, in which both these risks may be reduced. Another common infarct type in the MCA territory is lacunar infarction. Lacunes are generally caused by lipohyalinosis of small lenticulo- striate arteries, and thrombosis probably plays only a minor role in their eventual occlusion.

.ic

D. Herderscheg’, M. Limburg’, E. A. van Royen’, A. Hijdra’, H. R. Biller3, P. A. Koster4 Departments of ’ Neurology, Nuclear Medicine,

Centre of Hemostasis, Thrombosis and Athe- rosclerosis, Diagnostic Radiology, Academic Medical Centre, Amsterdam, The Netherlands

Key words: plasminogen activator, tissue- type; tomography, radionuclide computed; cerebral infarction

D. Herderschek, Department of Neurology H2- 214, Academisch Medisch Centrum, 1105 AZ Amsterdam, The Netherlands

Accepted for publication October 29, 1990

Hence, early reperfusion in large ischemic MCA- lesions may be dangerous (edema formation and herniation; induction of hemorrhage) and fibrinoly- tic treatment may not be effective in patients with lacunar infarction. Consequently, patients with ischemic lesions of an intermediate size would be most suitable for the evaluation of fibrinolytic therapy.

Selection of such patients may not be reliable when based on clinical signs only and the site of an angiographically demonstrated occlusion correlates poorly with the extent of the ischemic brain area (6). Perfusion defects can be reliably demonstrated at an early stage, when no structural damage is present, with regional cerebral blood flow studies using Single Photon Emission Computed Tomography (rCBF- SPECT). In a previous study we found that all patients with an initial maximum MCA defect on rCBF-SPECT died from herniation and patients who on a later CT proved to have a lacunar infarct had only minor or no initial SPECT-abnor- malities (7).

On the basis of these considerations we performed a pilot study of rtPA treatment in MCA-ischemia and used SPECT for selection of patients and docu- mentation of reperfusion. This report describes the results in the first five patients.

317

HerderscheG et al.

Material and methods

Patients. Consecutive patients, admitted with acute ischemia of the MCA territory underwent immediate CT-scanning and rCBF-SPECT if they met the following inclusion criteria: stable or progressing clinical signs of focal cerebral ischemia, with at least a hemiparesis; age over 18 and under 75 years; and possibhty to administer rtPA within 6 h after onset of symptoms. Patients with disabling previous stroke or chronic disabling disorders, or with one of the classic lacunar syndromes (8), and patients who used anticoagulants were excluded.

rCBF-SPECT studies. rCBF-SPECT was per- formed immediately after admission and always within 6 h after onset of symptoms. Imaging was 10 minutes after the intravenous injection of

550 to 750 MBq Technetium-99 m-labelled hexa- methylpropyleneamine oxime (TcHMPAO). A ro- tating gamma camera (Technicare, Omega 500) fitted with a 30" slant hole collimator was used. After attenuation correction, hard copies of the images, with a lower threshold set at 30% of the maximum pixel value, were analyzed. The cerebral flow deficits were measured in a semiquantitative way, by dividing each of the six axial slices of one examination into 12 equal radial sections. Two ob- servers jointly scored decrease of activity in each section compared with that of its opposite counter- part. The score ranged from zero (no right-left differ- ence in activity), to three (complete lack of activity in one section). The sumscore of all axial slices indi- cates both size and intensity of the lesion. Patients with normal SPECT and those with maximum de-

Fig. 1 . CT-scan (above) and rCBF-SPECT (below) of Patient 1, before (left) and after (right) treatment. There is an old infarct in the right insular region. First SPECT was made 1 h and 45 min after onset of symptoms and the second SPECT was 27 h and 45 min later. For the first and second CT-scan these periods were respectively 1 h and 15 min and 24 h. Second CT shows a fresh infarct in the left MCA-territory. Second SPECT is essentially unchanged with flow of parts of the basal ganglia on the left side supplied by vertebro-basilar branches, as on the first examination.

318

Thrombolysis with recombinant tissue plasminogen activator

fects in the MCA territory (above 48 on our semi- quantitative scale, a figure derived from our previous experience) were included for rtPA treatment (7). The rCBF scans were repeated 24-36 h after the fist .

CT scans. A Computed Tomography (CT) scan within 6 h after stroke onset excluded other relevant pathology. CT scans were repeated 24 h after the rtPA treatment, five days later, and thereafter when indicated.

Therapeutic intervention. Recombinant tPA was administered intravenously. In all patient a total dose of 100 mg was used. In the first 3 patients, after a bolus injection of 10 mg, infusion was continued with 50 mg in the first hour, followed by 20 rng in the second and third hours. In the last two patients it was given as a bolus of 15 mg, followed by 50 mg in the f i s t 30 min, and 35 mg in the next hour.

After rtPA acetylsalicylic-acid (ASA) 500 mg was administered orally or intravenously, followed by heparin during five days to prevent re-occlusion. The study was approved by the hospital ethics committee. Before treatment informed consent was obtained from all patients.

Coagulation studies. Before and 12 h after treatment blood was drawn for determination of plasrninogen and alpha-2-antiplasmin using methods as described before (9).

Results

From November 1988 to May 1989 six patients who met the entry criteria for fibrinolytic treatment were screened with rCBF-SPECT. One patient was excluded because a complete MCA flow deficit was found. She died after nine days following trans-

Fig. 2. CT-scan (above) and rCBF-SPECT (below) of Patient 2, before (left) and after (right) treatment. First SPECT was made 4 h and 45 min after onset of symptoms and the second SPECT was 33 h and 35 min later. For the first and second CT-scan these periods were respectively 3 h and 15 min and 23 h. A left temporoparietal perfusion defect on the first scan causing significant asymmetry between left and right hemisphere, is not present on the post-treatment scan.

319

HerderscheC et al.

tentorial herniation because of ischemic edema. Clinical findings, treatment delay, complications and outcome for all treated patients as well as results of rCBF-SPECT and coagulation studies are sum- marized in the Table.

Case histories

Case 1. A 62-year-old woman, who had a small rightsided brain infarct with transient signs six years before and atrial fibrillation since 4 years, and who was treated with ASA and digoxin, suddenly developed a severe left hemisphere deficit. She did not improve with rtPA treatment. For logistic reasons, this was the only patient in whom serial transcranial doppler sonography (TCD) could be performed. Initial TCD sonography yielded no signal from the left middle cerebral artery; 10 hours later a fast flow signal was detectable. On CT-scanning after 24 h the infarct was visible, hemorrhagic transformation was depicted on the fifth day, without clinical deterioration. After 17 days, she developed a large, right-sided MCA-infarct, demon- strated with CT. Death followed an arterial occlusion of the left leg, six weeks after admission. Autopsy was not permitted (Fig. 1). Case 2. A 72-year-old man was admitted with a non-fluent aphasia with comprehension deficit and a

Table 1. Summary of clinical and laboratory data of 5 patients treated with rtPA

paresis mainly of the right hand and arm. One hour after start ofrtPA and six and a halfhours after onset of deficit a rather sudden improvement set in with restoration of normal function within two hours. Half a year later neurologic function is normal (Fig. 2). Case 3. A 65-year-old man suddenly developed a severe non-fluent aphasia, comprehension defect, and a right sided hemiparalysis. Heparin following the rtPA treatment was discontinued when hematu- ria developed after 2 days. Neurological status was unchanged after treatment. Case 4. A 59-year-old woman became suddenly un- responsive, with a severe left hemisphere deficit. rtPA treatment was uncomplicated but there was no improvement. After two days a gradual deterioration set in with signs of transtentorial herniation. A CT- scan demonstrated massive edema. She died five days after stroke onset. At autopsy a large infarction in the MCA territory was found, with signs of trans- tentorial herniation. There was no hematoma. All large arteries were patent and small cortical pete- chiae in the ischemic area suggested breakup of an embolus . Case 5. A 73-year-old woman with Takayashu’s disease, atrial fibrillation, and an episode of amauro- sis fugax several years before used ASA 1OOOmg daily and a calcium entry blocker. Following a left

Cases

1 2 3 4 5

Delay stroke onset-treatment

Initial deficit

Clinical change

Complications

1 month outcome

Plasminogen (% of control) before/ 12 h after

Alpha-2-anti-plasmin I% of control) before/ 12 h after

SPECTdefect (semiquantitative scale; see text) before124 h after

3 h

Lethargy aphasia hem- ianopia hemiparalysis

None

None

Severely disabled; b e dridden

130/67

115/31

41/35

5 h 5 h 30 min 50 min

Aphasia hemiparesis Aphasia hemianopia hemiparalysis

Recovered completely None

None Hematuria after 3 days

Normal function Severely disabled: wheelchair; constant help

93/52 115/62

90132 98/35

1110 29/71

4 h 30 min

Somnolence aphasia hemianopia hemiparaly- sis incontinence

None

None

Dead after 5 days

106/61

93/38

45/54

3 h 30 min

Neglect hemianopia hem- iparesis forced deviation

None

Rebleeding of wounds; transfusion

Moderately disabled; walks without help; ADL- dependent

85/56

84/34

39/14 -

320

Thrombolysis with recombinant tissue plasminogen activator

sided paresis she fell, and sustained several bruises and bleeding wounds of the feet. After rtPA the bruises became frank hematomas and bleeding of the foot wounds started again. Heparin was stopped and blood was administered. Neurological condition was unchanged.

rCBF-SPEC1 results

See Table for quantification of the flow deficits. In Case 2 the image normalized (Fig. 2), in Case 5 the deficit decreased, and in Case 3 the deficit increased. Case 4 had a large flow deficit consisting of almost the complete MCA territory, but with a score (45) which was just below the cut-off value of 48.

Discussion

In a period of 6 months, five of total of 83 patients admitted with ischemic stroke could be treated with rtPA according to our protocol. The extent of ischemia as determined by rCBF-SPECT covered most of the MCA-territory in four patients, sug- gestive of an occlusion of the internal carotid artery or the MCA-stem. In Case2, rCBF-SPECT demonstrated a smaller lesion, compatible with an MCA-branch occlusion. Only this patient recovered completely after treatment. On the basis of natural history studies (10, 11) it can be estimated that the chances for complete recovery within 24 h in this patient without treatment were approximately 5 %. Furthermore, recovery occurred suddenly during rtPA-infusion, and was complete within a short time. The treatment may therefore well be responsible for his recovery.

Why did none of the other patients improve after treatment? There may be two possible explanations. First, arterial clots may not have been dissolved, even with the sufficient fibrinolysis achieved in all patients as revealed by the serial coagulation studies. With the treatment regimen we used arterial patency is not achieved in 30-40% of patients with myocardial ischemia (12, 13). Our four patients pre- sumably had ICA or MCA-stem occlusions, and these vessels may be too large for successful re- canalisation with this regimen. This is, of course, an important issue, which is not addressed by our approach, and should be studied with serial arterio- graphy. We have personal experience with two cases with complete basilar artery occlusion, in whom the same treatment regimen did succeed in recana- lisation (documented with serial angiography) and complete recovery in one, but not in the other (14). Differences in clot composition with ensuing differ- ential sensitivity to lysis with rtPA have been sug- gested as a possible explanation (15).

In Case 1 reperfusion was documented with TCD,

but no clinical improi-ement, nor improvement on rCBF-SPECT occurred. This observation may represent another explanation for treatment failure: reperfusion was achieved too late to restore function. The perfusion defect on rCBF-SPECT remained, either because the microcirculation is not restored (a well known early post-ischemic phenomenon), or because metabolism is not restored (intact metabo- lism is required for uptake of the radio-pharmaceuti- cal). In Case 3 the rCBF deficit even increased, while his clinical condition remained unchanged. The ini- tial SPECT demonstrated an area of intense hyper- fixation on the anterior border of the flow dis- turbance (an abnormality not accounted for in our SPECT-grading system), which was completely devoid of activity 24 h later. Initial hyperfixation is a well known phenomenon in cortical infarcts and may represent viable but non-functioning tissue (16). In our patient rtPA treatment obviously did not reverse this situation to normal.

Could the death of Case 4 be attributed to rtPA- induced reperfusion? Reperfusion was achieved, since at necropsy, 5 days after stroke onset, the large arteries were patent. This may or may not have been the result of rtPA treatment, considering the natural course of embolic occlusion. From the initial rCBF- deficit on SPECT we did not expect massive swelling to occur, because it was just below the cut-off value we considered safe (7). This value, however, is derived from a group of patients scanned within 24 h after onset of symptoms, and may not be valid for very early rCBF-SPECT (7). On second SPECT the defect was considerably larger and well above our cut-off value, but the increase can be explained by swelling of the ischemic region. The fact remains that Case4 had the largest initial defect of all, repre- senting a near complete MCA flow deficit. The clini- cal course, with extensive ischemic edema and death from transtentorial herniation can then be expected, irrespective of any treatment initiated after several hours. We believe that this must be the explanation for the two patients reported with fatal brain edema after rtPA treatment (4).

Why was the substantial decrease in flow deficit after treatment of Case 5 not accompanied by clini- cal recovery? On later CT this patient had a large deep infarct, which spared the cortical surface but included the internal capsule. Reversal of the initial cortical ischemia could therefore not result in clinical recovery.

In all patients the same dose of rtPA was used, although the infusion time was 3 h in the first three and 90 min in the last two. Cardiologic experiences with this shorter regimen, suggesting a higher patency rate, became available during our study (13). Coagu- lation studies of alpha-2-antiplasmin, plasmhogen and fibrinogen after 12 h were compatible with a

321

HerderscheC et al.

moderate level of a systemic fibrinolysis. Bleeding and bruising were minor, except in Case5, who needed a transfusion. In the patient who came to autopsy no internal bleeding was observed. In Case 1, second posttreatment CT-scanning showed hemorrhagic transformation of the infarct, but clini- cal status was unchanged.

These early experiences with rtPA in ischemic stroke do not allow firm conclusions about safety and effectiveness. Probably, recanalisation cannot be achieved in all patients, and even when it is achieved, does not always lead to clinical improve- ment. For selection of patients who may benefit from early thrombolysis, more experience with explanato- ry methods like SPECT and angiography is needed before the effectiveness of rtPA treatment can be proved in larger controlled trials.

Acknowledgements

The support and advice of Dr. R van To1 From Boehringer- Ingelheim is gratefully acknowledged. This study was supported by Boehringer Ingelheim, Alkmaar, The Netherlands

References

1. HACKE W, ZEUMER H, FERBERT A, BRUCKMANN H, DEL ZOPPO GJ. Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke 1988: 19: 1216-1222.

2. MORI E, TABUCHI M, YOSHIDA T, YAMADORI A. Intracaro- tid urokinase with thromboembolic occlusion of the middle cerebral artery. Stroke 1988: 19: 802-812.

3. VERSTRAETE M, BORY M, COLLEN D et al. Randomised trial of intravenous recombinant tissue-type plasminogen activator versus streptokinase in acute myocardial in- farction. Lancet 1985: 842-847.

4. KOUDSTAAL PJ, STIBBE J, VERMEULEN M. Fatal ischemic brain edema after early thrombolysis with tissue plasmino- gen activator in acute stroke. Br Med J 1988: 297:

5. OKADA Y, YAMAGUCHI T, MINEMATSU K et al. Hemorr- hagic transformation in cerebral embolism. Stroke 1989: 20:

6. BOZZAO L, FANITOLOZZI LM, BASTIANELLO S, BOZZAO A, FIESCHI C. Early collateral blood supply and late paren- chymal brain damage in patients with middle cerebral artery occlusion. Stroke 1989: 20: 735-740.

7. LIMBURG M, VAN ROYEN EA, HIJDRA A, DE B R U ~ N E JF, VERBEETEN BWJ. Single-photon emission computed tomo- graphy and early death in acute ischemic stroke. Stroke

8. FISHER CM. Lacunar strokes and infarcts: A review. Neurology 1982: 32: 871-876.

9. AVVISATI G, TEN CATE JW, BOLLER HR, MANDELLI F. Tranexemic acid for control of haemorrhage in acute promyelocytic leukemia. Lancet 1989: 2: 122-124.

10. LEVY D. How transient are transient ischemic attacks? Neurology 1988: 38: 674-677.

11. WERDELIN L, JUHLER M. The course of transient ischemic attacks. Neurology 1988: 38: 677-680.

12. MARDER VJ, SHERRY S. Thrombolytic therapy: current status (first of two parts). N Engl J Med 1988: 318:

13. NEUHAUS KL, FEUERER W, TEBBE U, JEEP-TEBBE S, VOGT A, TEBBE U. Improved thrombolysis with a modified dose regimen of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1989: 14: 1566-1569.

14. HERDERSCHEB D, LIMBURG M, HIJDRA A, KOSTER PA. Recombinant tissue plasminogen activator in two patients with basilar artery occlusion. J Neurol Neurosurg Psychiatry

15. JANG IK, GOLD HK, ZISKIND AA, FALLON JT, HOLT RE, LEINBACH RC, MAY JW, COLLEN D. Differential sensitivity of erythrocyte-rich and platelet-rich arterial thrombi to lysis with recombinant tissue-type plasminogen activator. Circu- lation 1989: 79: 920-928.

16. OLSEN TS, LARSEN B, SKRIVER EB, HERNING M, ENRVOLDSEN E, LASSEN NA. Focal cerebral hyperaemia in acute stroke. Stroke 1981: 12: 598-607.

1571-1 574.

598-603.

1990: 21: 1150-1155.

15 12-1 520.

1991: 54: 71-73.

322