Methods

We hypothesized that ERIS associated with IVT should occur during or within hours after termination of tPA infusion. Surveillance for ERIS or SICH was limited to 24 hours after IVT, a time window also adopted by the Prolyse in Acute Cerebral Thromboembolism (PROACT) trial.⁸

Patients with neurological deterioration causing a ≥4-point worsening on the National Institutes of Health Stroke Scale (NIHSS) were further evaluated. ERIS was defined as the occurrence of new neurological symptoms suggesting the involvement of initially unaffected vascular territories and evidence of corresponding ischemic lesions on cranial computed tomography (CCT) scans, in the absence of ICH. Neurological deterioration and evidence of appropriately located ICH on CCT, magnetic resonance imaging (MRI) scans, or both was diagnosed as SICH.

Data collected included patient age, sex, NIHSS score on admission, latency between symptom onset and initiation of IVT, and latency between initiation of IVT and neurological deterioration.

Results

A total of 372 patients were treated with IVT during the observation period; 31 of them were excluded for not meeting the NINDS criteria (time window >3 hours); no ERISs and 1 SICH (3.2%) were diagnosed in these patients. Thus, 341 (92%) patients were further evaluated (Aarau, n=52; Basel, n=89; Bern, n=7; Münsterlingen, n=17; St Gallen, n=52; Triemli, n=24; Zürich, n=94; and Waid, n=6). There were 212 men and 129 women, aged 66±15 years (range, 16 to 94 years). NIHSS score on admission was 13 (median; 95% CI, 12 to 14; range, 2 to 25). Latency between symptom onset and initiation of treatment was 153±29 minutes (range, 10 to 180 minutes).

Recurrent Ischemic Stroke

ERIS was diagnosed in 2 (0.59%; 95% CI, 0.07% to 2.10%) patients. The first was a 72-year-old man with a history of diabetes mellitus and arterial hypertension who was admitted with a dense right hemiparesis, hemihypesthesia, dysarthria, and fixed eye deviation to the left (NIHSS score, 16). Findings from the ECG and baseline CCT were normal. IVT was initiated 170 minutes after symptom onset. Forty minutes later, his level of consciousness rapidly decreased, and the patient became comatose. IVT was discontinued, and CCT performed immediately after neurological deterioration was still unremarkable. The third CCT performed 21 hours after the onset of initial symptoms showed multiple ischemic lesions in the territories of the left middle (with hemorrhagic transformation), anterior cerebral, and anterior choroidal arteries with compression of the left lateral ventricle and temporal horn; a midline shift and trans-tentorial herniation leading to displacement of the pons to the right side and compression of the fourth ventricle; ischemic lesions in the right middle cerebral artery (MCA); and probable ischemic lesions in the medial branch of the right posterior inferior cerebellar artery (Figure). Lesions in the territory of the right MCA and right posterior inferior cerebellar artery were not compatible with the initial symptoms. The patient died 3 days after symptom onset. Necropsy was not permitted.

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Axial CT scan of the brain 12 hours after IVT with tPA in a patient who became comatose 40 minutes after initiation of thrombolytic treatment, showing acute ischemic lesions in the territories of the left middle cerebral, anterior cerebral, anterior choroidal, and right middle cerebral arteries and the medial branch of the right posterior inferior cerebellar arteries.

The second patient was a 78-year-old woman admitted with dysarthria, left-sided weakness, hemihypesthesia, and hemianopia (NIHSS score, 11). The past medical history was unremarkable except for arterial hypertension. The ECG showed no ischemic changes but revealed a first-degree atrioventricular block; mediastinal widening was diagnosed on chest radiography. After normal CCT findings were observed, IVT was initiated 175 minutes after symptom onset. Fifty minutes after IVT initiation, the patient became comatose and developed generalized tonic seizures. IVT was discontinued. Findings on the emergency CCT were normal. CCT performed 6 hours after onset of the presenting stroke revealed an ischemic lesion in the territory of the right MCA and early demarcation of a further ischemic lesion in the territory of the left MCA. Bilateral occlusion of the internal carotid arteries was diagnosed on CCT angiography; this was presumed to be acute, as homogeneous, fresh, mainly hypoechogenic thrombus was visualized in the lumen of both internal carotid arteries on extracranial color duplex sonography. The patient’s presenting symptoms were compatible with the diagnosed ischemic lesion in the territory of the right MCA but not with the second contralateral ischemic lesion. Abdomen and chest CT scans did not confirm the suspected aortic dissection but showed multiple, bilateral, acute kidney infarcts. The patient died on the third day after symptom onset. Necropsy was not permitted.

Discussion

The present study is the first report of ERIS in patients with acute ischemic stroke treated with IVT; furthermore, the size of the present study and the fact that it presents population-based data from patients receiving tPA under a predefined protocol allow valid conclusions concerning its incidence. Although recurrent ischemic stroke was assessed in the NINDS trial, the time point of neurological deterioration was not specified, and the pathophysiological mechanism proposed in the present study was not postulated.

The diagnosis of ischemic lesions in multiple cerebral vascular territories in 1 patient and in both MCA territories and both kidneys in the second patient are highly suggestive of the disintegration and subsequent scattering of cardiac or aortic thrombi as the underlying etiology of ERIS. Obviously, disintegration of thrombi can occur spontaneously and is not necessarily associated with tPA administration. Still, the fact that neurological deterioration occurred 40 to 50 minutes after tPA initiation in both cases strongly argues for a causative role of tPA. The only possible means for resolving this issue would be a randomized study comparing the incidence of ERIS between stroke patients treated with IVT and controls; still, such a study would not be ethical, taking into account that IVT constitutes a treatment of proven efficacy for patients with acute ischemic stroke. A registry of patients with ERIS after IVT could provide more information on this intriguing issue.

Unfortunately, no necropsy was performed in the 2 patients; the same was true for echocardiography, which was withheld owing to the lack of therapeutic consequences. We can thus provide no evidence of underlying cardiac or aortic disease to support our hypothesis. Considering that the cause of ERIS both from the clinical and the imaging viewpoint was clearly embolic, it is questionable whether this information would be of great assistance, the basic unanswered question being the causative role of tPA rather than the source of embolic material.

Previous coronary thrombolysis trials reported a 0.4⁹ to 0.7%¹⁰ incidence of ischemic stroke until hospital discharge or for the following 30 to 35 days. Only 1 study described the incidence of ischemic stroke within the first 6 hours after thrombolysis, which was 0.13%.¹⁰ Comparison of these results with those of the present study is inconclusive, owing to differences in treatment protocols with regard to the dose and duration of tPA infusion and the concomitant use of aspirin, heparin, or both. Furthermore, CCT scans were not always part of the diagnostic work-up for presumed stroke in coronary trials, rendering the determination of true ischemic stroke prevalence impossible.

Obviously, the incidence of ERIS is far too low to justify delay of IVT initiation, considering the demonstrated higher benefit associated with earlier IVT treatment.¹¹ Furthermore, transesophageal echocardiography, the sole method capable of excluding the possibility of intracardiac or aortic thrombi, can barely be performed within the 3-hour window and is not available on a 24-hour basis. We must point out, however, that the true incidence of ERIS was potentially underestimated in this study, because we evaluated only those patients with a deterioration ≥4 points on the NIHSS.

Although the differences in temporal occurrence of ERIS and SICH are intriguing, they obviously do not allow a definite distinction between these 2 entities in an individual patient. Thus, neurological deterioration should prompt discontinuation of IVT and performance of an urgent CCT scan. Our findings should alert treating physicians to the possibility that deterioration during IVT is not necessarily due to ICH but can also be caused by ERIS. We propose that patients with ERIS should undergo urgent diffusion- and perfusion-weighted MRI to estimate the extent of both the ischemic lesions and the associated penumbra. The results of these MRI studies will be helpful to guide patient management, in particular, to resolve the question of whether further therapeutic regimes such as local intra-arterial or mechanical thrombolysis should be taken into consideration. Exclusion of SICH in these cases should by no means prompt a wait-and-see attitude.