Introduction
Treatment of acute ischemic stroke with intravenous (i.v.) thrombolysis within the first 4.5 h from symptoms onset is often effective [1], but some patients may worsen during recombinant tissue plasminogen activator (rt-PA) administration or later, after improvement [2]. Early recurrent ischemic stroke on the previously unaffected side may be suggestive of embolism from fragmentation of a pre-existing cardiac thrombus in patients with paroxysmal atrial fibrillation (PAF). In particular, left appendage is the privileged site for thrombus formation in these patients, when transthoracic echocardiography (TTE) is negative for intracardiac thrombus [3]. However, this complication is generally not reported because it is impossible to demonstrate a left appendage clot by TTE in the acute phase of stroke and transesophageal echocardiogram (TEE) is not usually performed during the acute phase of stroke [3].
We report two very unusual cases of thrombolysed stroke patients, with PAF but normal sinus rhythm on admission, who respectively developed early recurrent ischemic stroke within few hours after complete improvement and during i.v. rt-PA administration. i.v. thrombolysis was early repeated off-label after TEE evidence of left appendage thrombus in the first patient. Instead, i.v. rt-PA infusion was suspended in the second patient, and fragmentation of probable left appendage thrombus could be the possible cause of early recurrent cardioembolic stroke during i.v. thrombolysis.
Case 1
A 75-year-old woman acutely developed dysarthria, slight paresis and hypoesthesia of the left lower limb. She had past history of hypertension and PAF, and had a cardiac pacemaker for atrioventricular block. On admission, her blood pressure was stable and heart rhytm was sinus. National Institute of Health Stroke Scale (NIHSS) score was 4. Brain computed tomography (CT) scan resulted negative for recent vascular lesions. Doppler ultrasound imaging showed no relevant stenosis of internal carotid arteries. TTE revealed severe dilatation of left atrial with slight mitral failure, without intracardiac thrombus. i.v. thrombolysis (7 mg rt-PA as a bolus and 60 mg infusion for 1 h immediately after the bolus therapy) was started 175 min after symptoms onset with patient consent to treatment. NIHSS score was 0 at 24 h. Postprocedure CT scan excluded brain haemorrhage and angiographic CT excluded stenosis of intracranial arteries. The pacemaker recording control had detected an atrial fibrillation lasting about 48 h 7 days before stroke onset. Thirty hours after i.v. thrombolysis, TEE showed a large left appendage thrombus (Fig. 1) and an antithrombotic treatment with heparin was immediately started. Three hours later, the patient acutely developed drowsiness, severe aphasia, right hemianopia, severe right emiparesis, slight hypoesthesia of the right limbs, without any significant change in blood pressure. NIHSS score was 15. Brain CT scan showed no haemorrhagic complications or direct or indirect signs of recent ischemic lesions. Activated partial thromboplastin time was 1.12. After a thorough evaluation of both pros and cons, regarding mainly the clinical severity of the second ischemic stroke and the presumed higher risk of bleeding, we decided to administer a second full dose of rt-PA with patient consent to treatment. i.v. thrombolysis started 35 min after the sudden neurological deterioration. NIHSS was 1 at 1 hour after the second i.v. rt-PA, 1 at 24 h and 0 at 7 days later.
Case 2
A 76-year-old woman acutely developed afasia and right hemiparesis. She had past history of hypertension, hyperlipidemia, PAF and she had a cardiac pacemaker for atrioventricular block. On admission, her blood pressure was stable and heart rhytm was sinus. NIHSS score was 9. Brain CT showed old ischemic areas. TTE revealed hypocinetic dilatative cardiomyopathy (ejection fraction of 38%), without intracardiac thrombus. i.v. thrombolysis (5 mg rt-PA as a bolus and 45 mg infusion for 1 h immediately after the bolus therapy) was started 150 min after symptoms onset with patient consent to treatment. Thirty minutes later, the patient suddenly deteriorated with stupor, left hemiplegia, left hemianopia, right eyes and head lateral deviation (NIHSS score: 28). Patient's blood pressure was stable and heart rhytm was sinus. rt-PA was discontinued after 60% delivering. CT scan excluded brain haemorrhage. Control TTE was negative for intracardiac clots. Extracranial Doppler sonography revealed an irregular atherosclerotic plaque producing 70% stenosis of the origin of left internal carotid artery (ICA), but no haemodynamically significant stenosis of right ICA. Transcranial Doppler sonography demonstrated an intracerebral altered blood flow velocity in right M1 middle cerebral artery (MCA), whereas left M1-MCA was obstructed. Three hours and 30 min after symptoms onset, diffusion-weighted MRI demonstrated recent ischemic areas in left capsular–thalamic and right frontal–temporal region. MRI angiography showed occlusion of the right M2-MCA and left M1-MCA. The pacemaker recording control has detected an atrial fibrillation lasting about 48 h 3 days before stroke onset. Twenty-four hours later, NIHSS score was 31 and brain CT confirmed the presence of recent ischemic areas in the left capsular–thalamic region and right MCA territory, with oedema and shift of median structures. Neurological conditions remained unchanged and the patient died 17 days after onset.
Discussion
Neurological deterioration during i.v. rt-PA administration or deterioration following improvement after i.v. thrombolysis are not rare events [2]. Instead, early recurrent ischemic stroke, which is defined as acute ischemic stroke involving an initially unaffected independent arterial territory, is rare in patients treated with i.v. rt-PA [4]. This is not explained by either reocclusion of thrombosed intracranial vessels, or reperfusion injury, or symptomatic artery-to-artery embolism from a proximal source, or brain oedema or cerebral hypoperfusion due to cardiopulmonary decompensation with drop of blood pressure in the territory of carotid stenosis [4].
Early recurrent ischemic stroke on the previously unaffected side has very rarely been described during or after i.v. rt-PA for acute ischemic stroke [4–6]. This event is more suggestive of embolism from fragmentation of a pre-existing intracardiac thrombus, but the cardioembolic source is speculative without TEE [3].
A very recent study showed an association between early recurrent ischemic stroke and previous AF, but TEE was not performed [4]. AF is a major cause for formation of left atrial appendage thrombus, which may be a possible source of embolic fragmentation during or after rt-PA administration in acute ischemic stroke. However, the potential risk of early recurrent ischemic stroke due to left appendage thrombus after i.v. thrombolysis is generally not discussed in patients with PAF but normal sinus rhythm on admission because the diagnosis of PAF is unlikely on admission with single ECG recordings and TTE is not useful to detect a thrombus in this site in the acute phase of stroke [4].
We report two very uncommon cases of acute ischemic stroke patients, with PAF but normal sinus rhythm on admission, who show the ‘Dr Jekyll’ or ‘Mr Hyde’ side of i.v. thrombolysis on early recurrent cardioembolic stroke.
The case 1 has been effectively treated with a second i.v. thrombolysis after 30 h from the first. This patient presented early recurrent stroke with deterioration following complete improvement after the first i.v. thrombolysis. It's known that rt-PA induces a suppression of the t-PA concentration and a massive activation of coagulation factors and fibrin formation within the first hours after treatment, which persists for up to 3 days [7]. These rt-PA-induced blood abnormalities may contribute to the early reocclusion after successful thrombolysis or a recurrent stroke [7]. However, we hypothesize that left appendage thrombus, which was detected by TEE after the first thrombolysis, was the embolic source of early ischemic recurrent stroke after antithrombotic therapy onset. It is probably that left appendage thrombus was not dissolved by the first thrombolysis because of large size and short interval between first and second stroke, and, therefore, it was also the cause of first ischemic stroke. In this regard, thrombolytic therapy is an option for treating a left atrial thrombus [8], although the effectiveness and risk of thrombolytics for an organized or partially organized thrombus or thrombi of longer duration is not known clinically [8]. This case emphasizes the ‘Dr Jekyll side’ of i.v. thrombolysis on early recurrent ischemic stroke and suggests the possible repetition of i.v. rt-PA within few hours for deterioration following after complete improvement in cardioembolic patients with CT scan negative for recent vascular lesions. A possible limitation might be that early recurrent stroke was only clinically defined in the case 1. However, brain MRI is not required before i.v. rt-PA onset according to the i.v. thrombolysis guidelines for acute ischemic stroke.
The case 2 showed early recurrent ischemic stroke with neurological deterioration during i.v. rt-PA, which has been suspended before the complete administration. We suppose that a cardioembolic source was the likely cause of early recurrent ischemic stroke during i.v. thrombolysis, also in this case. In fact, CT scan was negative for brain oedema or haemorrhage after thrombolysis, artery-to-artery embolism unstable plaque was excluded and patient's haemodynamic conditions were stable. It was possible that the cardioembolic source of the right MCA occlusion was a small left appendage thrombus because pacemaker recording control has detected a PAF 3 days before stroke onset and TTE was negative for intracardiac thrombus in the acute phase. We explain early recurrent ischemic stroke during i.v. thrombolysis with a possible fragmentation of small left appendage clot by rt-PA, although TEE was not performed because of the patient's clinical condition. This case emphasizes the ‘Mr Hyde side’ of i.v. thrombolysis on early recurrent ischemic stroke and show the risk of neurological deterioration during i.v. rt-PA administration in PAF patients with presumed cardioembolic source.
TEE is the only procedure to rule out the presence of left appendage thrombus [3], but it is not always practicable in the acute phase of stroke.
Clinical guidelines don’t clearly specify how to proceed in thrombolysed patients with early recurrent ischemic stroke. A repetition of i.v. thrombolysis within few hours after the first is considered off-label, basing on current protocols [1]. In fact, any previous stroke within the last 3 months is listed as a contraindication for i.v. rt-PA and the risk of symptomatic haemorrhage after repeating i.v. rt-PA within a short interval is completely unknown. However, a second i.v. thrombolysis should not reinforce the fibrinolytic effect of first i.v. rt-PA infusion because rt-PA has a very rapid clearance time (about 15 min after infusion) and short half-life (4–5 min) [9]. It may be well tolerated and effective to repeat i.v. thrombolysis within few hours or days for early recurrent ischemic stroke, although only isolated cases have been reported [10–12].
The discontinuation of i.v. rt-PA administration for neurological deterioration can be considered a reasonable procedure. We suggest that i.v. thrombolysis should not be restarted in early recurrent ischemic stroke patients who present no complete improvement before neurological worsening. Bridging i.v. intra-arterial treatment may be an effective therapeutic option, reducing presumed cardioembolic risk from systemic fibrinolytic effects in patients with FAP. Mechanical thrombectomy may also prove to be an alternative treatment in these patients. However, these endovascular recanalization techniques may be associated to severe complications.
Conclusion
i.v. thrombolysis is the only approved specific therapy for acute ischemic stroke and the presence of cardiac thrombus is not an established contraindication. However, early recurrent ischemic stroke after i.v. rt-PA administration may be a rare adverse event in cardioembolic patients. For this exceptional condition, we suggest the repetition of i.v. thrombolysis in patients with complete improvement after the first stroke and brain CT scan negative after the second stroke, although this therapeutic approach remains off-label.
Acknowledgements
The corresponding author takes full responsibility for the data, the analyses and interpretation, and the conduct of the research. All authors have full access to all of the data, have seen and agree with the contents of the manuscript. The material submitted to Blood Coagulation & Fibrinolysis is not under review at any other publication. The authors have no financial interests to disclose.
Conflicts of interest
There are no conflicts of interest.
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