Abstract
The subset of patients who deteriorate after an apparently successful initial response to intravenous t-PA poses a management problem. Pathophysiologically, this scenario is likely to represent initial recanalisation in response to t-PA, followed by vessel re-occlusion. Possible therapeutic options include intraarterial thrombolysis, angioplasty and stenting, and repeat administration of intravenous thrombolysis. We describe a case in which this dilemma arose and discuss the issues surrounding clinical management.
Illustrative case history
A 73-year-old man presented with a 90-min history of sudden-onset weakness of the left face, arm and leg. He had a history of previous ischaemic stroke (from which he had made a full recovery 6 years previously), type 2 diabetes, hypertension, hyperlipidaemia and glaucoma.
Examination revealed a heart rate of 80 beats/min, sinus rhythm, blood pressure of 160/80 and normal heart sounds with no cardiac murmurs or carotid bruits. He was dysarthric with left facial weakness, left homonymous hemianopia and eye deviation to the right. He had a dense left arm weakness and moderate left leg weakness with neglect. NIHSS was 13 and initial computed tomography (CT) brain at 110-min post-stroke onset showed no acute changes. He was thrombolysed with rt-PA at 2 h and 30 min after onset of symptoms and by day 2 had made a full recovery to NIHSS = 0.
Investigation results
Carotid duplex performed on day 2 was a technically difficult study. There was possible occlusion of the right internal carotid artery (ICA). The left ICA was noted to be extremely narrow and it was not possible to accurately calculate the degree of stenosis. Transcranial Doppler ultrasound showed left to right crossflow via the anterior communicating artery. Subsequent CT angiogram of the neck confirmed a complete occlusion of the right ICA and a 99% stenosis of the left ICA.
Subsequent course
The treating team commenced an intravenous heparin infusion while awaiting urgent left carotid endarterectomy, which could not be performed until day 3. However, during the afternoon of day 2, the patient developed acute-onset dense left hemiparesis with neglect and gaze deviation to the right. Computed tomography scan of brain 45 min after onset of symptoms showed no acute changes and no ischaemic changes related to the previous infarct which had been treated with t-PA 40 h earlier.
Outcome
Discussion ensued as whether to repeat thrombolysis in view of the early time window and lack of tissue ischaemia on CT. It was decided to perform urgent angioplasty and stenting of the critically stenosed left ICA. The patient was preloaded with clopidogrel via nasogastric tube, and the left ICA was stented with good angiographic result within 3 h of the clinical deterioration. However, his neurological deficit failed to improve and repeat CT scan 24 h later showed a large right MCA territory infarct. He did not improve further and required nursing home care on discharge from hospital.
Discussion
Studies using transcranial Doppler ultrasound have shown that the outcome from intravenous t-PA relates to the degree of vessel recanalisation achieved (1). Doppler studies have reported a 34% rate of re-occlusion after initial recanalisation in t-PA-treated patients, associated with clinical evidence of deterioration after initial improvement in the majority of cases (2).
There is little evidence to guide management in this group of patients. The NINDS t-PA Stroke Study and most currently used protocols for thrombolysis cite ‘stroke within preceding 3 months’ as a contraindication (3). Prior transient ischaemic attacks are certainly not a contraindication, provided deficits have fully resolved; should an ischaemic stroke which has fully resolved with treatment be managed in the same fashion?
Topakian et al. (4) describe a case in which a patient was treated twice with t-PA within 90 h, with favourable outcome. In this case, the authors used DWI-PWI mismatch on MRI as a rationale for repeat therapy.
On a pathophysiological level, the main risks of repeat thrombolysis relate to the increased risks of intracerebral haemorrhage. Cerebral tissue which has been damaged by ischaemia has impaired adhesion between microvessel cells and the extracellular matrix, and increased capillary permeability, compounded by local inflammatory mediators, making the risk of parenchymal haemorrhage higher, although the magnitude of this risk is not known (5). In particular, it is not known whether the absence of established ischaemia on CT scan confers a better outcome from repeat thrombolysis.
The choice between thrombolysis and angioplasty has been more comprehensively investigated in patients with acute myocardial infarction. Primary percutaneous coronary intervention (where available) is now proven to be superior to thrombolysis (6). In centres where thrombolysis is the only treatment option, patients who fail to recanalise (as indicated by persisting ECG changes), are transferred for urgent coronary angioplasty, which has been demonstrated to be superior to repeat thrombolysis in terms of outcome, and is equivalent in terms of safety (7).
A number of groups have sought to investigate whether intravenous t-PA followed by urgent intravascular intervention or intra-arterial t-PA in nonresponders (defined clinically or by imaging with transcranial Doppler or angiography) would improve outcomes. The Interventional Management of Stroke Trial demonstrated the safety and feasibility of reduced-dose intravenous t-PA within 3 h of onset of stroke followed by intra-arterial thrombolysis, and demonstrated improved outcomes in the treatment group (8). However, the ideal study would be a randomised-controlled trial of standard-dose t-PA against either acute endovascular intervention or intravenous tPA plus subsequent vascular intervention in nonresponders; this study is yet to be conducted.