Advances in clinical and neuroimaging assessment of ischemic cerebrovascular disease combined with the expanding knowledge of the pathophysiology of human brain infarction led to a resurgence of enthusiasm for newer potentially safer thrombolytic agents and techniques in human ischemic stroke [17]. This renewed interest was greatly influenced by the animal studies outlined in Chap. 2. It was realized that earlier attempts initiated treatment too late (i.e., longer than 6–8 h and as long as beyond 2–3 days after the onset of symptoms). Beginning in the early 1980s, individual case reports documented clinical improvement from ischemic stroke following cerebral arterial recanalization with intra-arterial thrombolytic agents [18–20].

Abe et al. studied stroke patients using UK (60,000 IU/days) for 7 days or placebo in a double-blind protocol. Improvement in two of three clinical outcome scales was noted in the UK-treated group [21]. Fujishima et al. reported on 143 patients with cerebral infarction treated with either UK (2.83 × 10⁵ U iv over 6 h [n = 81] or a combination of UK-dextran sulfate [DS], 2.84 × 10⁵ U plus 300 mg DS over 1 day [n = 62]) in a multicenter cooperative study [22]. Only 89 % of the cases had head CT performed for stroke diagnosis and 30 % had spinal taps. Overall, clinical improvement rate and safety was reported in 74 % of UK-treated patients and 84 % of the UK-dextran-treated patients.

From 1983 to May 1986, Hacke et al. treated 43 prospectively studied patients with intraarterial UK or SK for angiographically documented vertebrobasilar artery territory thrombosis [23]. Heparin, 300 U/h, was routinely administered simultaneously with the thrombolytic agents and then administered at 1,000 U/h intravenously with hydroxylethyl starch. All patients without recanalization died, whereas 14 (74 %) of 19 who recanalized survived (p = 0.000007), 10 with a favorable outcome. Thrombolysis was avoided if the initial head CT showed hypodense areas in the brain stem or cerebellum. Four of the 43 cases developed hemorrhagic transformation: two of the four died. Fibrinogen, activated partial thromboplastin time, and fibrin split product measurement in the patients with hemorrhagic events were not different from the patients without ICH. Two of four with hemorrhagic infarction did not show recanalization. This study strongly suggested that recanalization of vertebrobasilar occlusions could be accomplished, and was associated with clinical salvage. Their expanded experience with 66 patients was also reported [24].

Data on local intra-arterial UK or SK for acute carotid territory stroke was reported by Del Zoppo et al. from a prospective, angiographically based, two- center open-pilot study [20]. The longest time from symptom onset to treatment time with complete recanalization was 10 h. Seventy-five percent (15 of 20 patients) with acute stable symptoms (mean treatment onset interval 7.6 h) demonstrated complete recanalization (unblinded evaluation) with 10 of 15 exhibiting clinical improvement by the time of hospital discharge. Four patients with hemorrhagic transformation had complete recanalization and were treated 6–10 h after symptom onset (all were also treated with heparin and hydroxyethyl starch). Three of these four patients showed clinical improvement. Although these data are often cited to support a claim that patients should not receive thrombolytic therapy beyond 6 h following stroke onset, three of the four hemorrhage patients actually improved.

Mori et al. reported 22 patients who received intracarotid UK for evolving cerebral infarction resulting from angiographically documented thromboembolic occlusion of the MCA or its major branches [25]. Five of six with investigator- rated excellent outcome were in the recanalized group, and the volume of CT infarction was significantly less in the recanalized group (35.5 ± 55.4 mL) compared with the nonrecanalized group (172.8 ± 122.6 mL) (p < 0.01). Prognosis was also correlated with restoration of blood flow (r = 0.60, p = 0.003). There was no correlation between initial neurological state and recanalization. Neither interval from onset to infusion nor dose of UK correlated with prognosis.

Terashi et al. treated 364 stroke patients with either t-PA (n = 171) or UK in a double-blinded protocol [26]. Of the total, 36 % started treatment within 24 h and 70 % within 48 h. There were no statistically significant differences between the two groups at the 7-day clinical evaluation. Adverse effects were noted in approx 10 % of each group, and the incidence of hemorrhagic infarction was less than 5 % in each group.

Hennerici et al. reported the results of administering 70 mg alteplase intravenously over 90 min in 19 patients with ischemic stroke of less than 24-h duration [27]. Full-dose intravenous heparin was also administered. One patient was excluded after entry because his symptoms were later determined to be of greater than 24-h duration. Of the other 18 patients, one sustained a fatal ICH, and early arterial recanalization was achieved in only 25 %. Nine additional patients died of complications of their entry strokes. The onset times of many of the patients could not be determined with certainty, and the authors proposed that delayed treatment may have contributed to the poor outcomes. They also suggested that the dose of alteplase was too low.

Later, von Kummer and associates reported on 32 patients with severe hemispheric deficits treated with a 100 mg of alteplase administered over 90 min, combined with a 5000 U bolus of intravenous heparin followed by a continuous infusion at 1,000–1,500 U/h, aiming to double the activated partial thromboplastin time in each patient [28]. All patients were treated within 6 h (mean ± SD = 3.8 ± 1.1 h) of stroke onset, and all had pretreatment CT scanning and cerebral angiography. Partial or complete recanalization of the infarct-related artery was documented angiographically in 34 % immediately after the recombinant tissue plasminogen activator (rt-PA) infusion, and in an additional 19 % within 12–24 h by predominantly transcranial Doppler assessment. Hemorrhagic transformation was observed in 38 %, of which one-fourth (9 %) was associated with neurological deterioration and death. At 4 week, clinical outcome was classified as good (ambulatory, National Institutes of Health [NIH] Stroke Scale score <13) in 44 % and poor or dead in the remainder. Good outcomes were correlated with recanalization within 24 h. Reocclusion was reported in one patient despite the heparin treatment. The authors acknowledged that their results did not show a clear benefit of concomitant heparin therapy, but suggested that it did not appear to be substantially more dangerous than t-PA alone.