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Clinical, Diagnostic, Treatment, and Outcome Data on the Patients*
Clinical, Diagnostic, Treatment, and Outcome Data on the Patients*
1.
Turney  TMGarraway  WMWhisnant  JP The natural history of hemispheric and brainstem infarction in Rochester, Minnesota. Stroke. 1984;15790- 794Article
2.
Hornig  CRBüttner  THoffmann  ODorndorf  W Short-term prognosis of vertebrobasilar ischemic stroke. Cerebrovasc Dis. 1992;2273- 281Article
3.
Labauge  RPages  MMarty-Double  CBlard  JMBoukobza  MSalvaing  P Occlusion du tronc basilaire. Rev Neurol. 1981;10545- 571
4.
Becker  KJPurcell  LLHacke  WHanley  DF Vertebrobasilar thrombosis: diagnosis, management, and the use of intra-arterial thrombolytics. Crit Care Med. 1996;241729- 1742Article
5.
The National Institute of Neurological Disorders and Stroke r-tPA Stroke Study Group, Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;3331581- 1587Article
6.
Lyden  PBrott  TTilley  B  et al.  Improved reliability of the NIH Stroke Scale using video training. Stroke. 1994;252220- 2226Article
7.
van Swieten  JCKoudstaal  PJVisser  MCSchouten  HJAvan Gijn  J Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19604- 607Article
8.
Brandt  Tvon Kummer  RMüller-Küppers  MHacke  W Thrombolytic therapy of acute basilar artery occlusion. Stroke. 1996;27875- 881Article
9.
Hacke  WZeumer  HFerbert  ABrückmann  Hdel Zoppo  GJ Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke. 1988;191216- 1222Article
10.
Zeumer  HFreitag  HJZanella  FThie  AArning  C Local intra-arterial fibrinolytic therapy in patients with stroke: urokinase versus recombinant tissue plasminogen activator (rt-PA). Neuroradiology. 1993;35159- 162Article
11.
Brandt  TPessin  MSKwan  ESCaplan  LR Survival with basilar artery occlusion. Cerebrovasc Dis. 1995;5182- 187Article
12.
Heiss  WDRosner  G Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol. 1983;14294- 301Article
13.
von Kummer  RForsting  MSartor  KHacke  W Intravenous recombinant tissue plasminogen activator in acute stroke. Hacke  Wdel  Zoppo GJHirschberg  Meds.Thrombolytic Therapy in Acute Ischemic Stroke New York, NY Springer Publishing Co Inc1991;161- 167
14.
Huemer  MNiederwieser  VLadurner  G Thrombolytic treatment for acute occlusion of the basilar artery. J Neurol Neurosurg Psychiatry. 1995;58227- 228Article
15.
Herderscheé  DLimburg  MHijdra  AKoster  PA Recombinant tissue plasminogen activator in two patients with basilar artery occlusion. J Neurol Neurosurg Psychiatry. 1991;5471- 73Article
16.
Kamps  IWeiss  JRingelstein  EB Repetitive Behandlung einer subtotalen vertebrobasilären Stenose mit "tissue plasminogen activator" (tPA). Nervenarzt. 1992;63755- 760
17.
Becker  KJMonsein  LHUlatowski  JMirski  MWilliams  MHanley  DF Intraarterial thrombolysis in vertebrobasilar occlusion. AJNR Am J Neuroradiol. 1996;17255- 262
Original Contribution
April 1998

Early Intravenous Thrombolysis With Recombinant Tissue-type Plasminogen Activator in Vertebrobasilar Ischemic Stroke

Author Affiliations

From the Department of Neurology, University Hospital of Cologne, Cologne, Germany.

Arch Neurol. 1998;55(4):466-469. doi:10.1001/archneur.55.4.466
Abstract

Background  The optimal therapy of vertebrobasilar ischemic stroke is under debate. In the case of underlying basilar artery occlusion, intra-arterial thrombolysis is recommended. Because this pathologic condition is rarely found and the procedure is time consuming and restricted to specialized centers, the question arises whether early intravenous thrombolysis could also effectively be applied in vertebrobasilar ischemic stroke.

Objective  To determine if early intravenous thrombolysis could be used effectively in vertebrobasilar ischemic stroke.

Design  A case series of 12 consecutive patients with acute vertebrobasilar ischemia were followed up 3 months after thrombolytic treatment at the Department of Neurology of the University Hospital of Cologne, Cologne, Germany, a primary care and referral center.

Methods  Patients with clinically diagnosed moderate to severe vertebrobasilar ischemic stroke with clearly determined symptom onset were treated with intravenous recombinant tissue-type plasminogen activator within 3 hours after symptom onset following a protocol similar to that of the National Institute of Neurological Disorders and Stroke study.

Results  On admission, 7 patients exhibited moderate to severe brainstem symptoms without impairment of consciousness and 5 patients had impairment of consciousness, of whom 2 were comatose. Of 12 patients, 10 had a favorable outcome after 3 months defined as full independence (Barthel index score of 100) or return to premorbid condition. One patient had a poor outcome with complete dependency due to reocclusion after primarily successful thrombolysis, and 1 patient died of severe brainstem infarction and additional space occupying parietal hemorrhage.

Conclusion  Favorable outcome could be achieved in the majority of 12 consecutive patients with moderate to severe vertebrobasilar ischemic stroke treated with intravenous recombinant tissue-type plasminogen activator within 3 hours after symptom onset.

VERTEBROBASILAR ischemic stroke accounts for about 20% of all ischemic strokes.1 An unfavorable outcome (major or fatal stroke) is found in as many as 60% of patients.2 In cases of basilar artery occlusion, mortality can be as high as 90%.3 Despite its poor prognosis, the optimal therapy of vertebrobasilar ischemic stroke remains undetermined.4

Angiography and, in cases of basilar occlusion, subsequent intra-arterial thrombolysis is considered the optimal management for vertebrobasilar ischemic stroke. However, intra-arterial thrombolysis is restricted to a few highly specialized centers only, and the procedure is time consuming. The time between onset of symptoms and the beginning of thrombolytic therapy is a crucial factor in the success of thrombolytic therapy. From the National Institute of Neurological Disorders and Stroke (NINDS) study5 we learned that intravenous thrombolysis can be used safely and effectively within 3 hours after symptom onset. Therefore, should patients with acute vertebrobasilar ischemia admitted to a hospital without angiography facilities within 3 hours after symptom onset be treated immediately with intravenous thrombolysis or transported to respective centers for intra-arterial thrombolysis?

We describe 12 consecutive patients with vertebrobasilar ischemic stroke treated with intravenous recombinant tissue-type plasminogen activator (rtPA) within 3 hours after symptom onset according to the NINDS criteria.5

PATIENTS AND METHODS

Between March 1996 and July 1997, we treated 93 consecutive patients with acute ischemic stroke with intravenous rtPA within 3 hours after symptom onset; of these, 12 patients had vertebrobasilar ischemic strokes.

The diagnosis of vertebrobasilar ischemic stroke was based on the presence of typical brainstem symptoms (eg, cranial nerve palsies, dysarthria, dysphagia, ataxia, pareses, and impairment of consciousness). Occlusion of the basilar artery was not documented before treatment.

Inclusion and exclusion criteria were adopted from the NINDS study.5 Patients were not included if the onset of symptoms could not be defined precisely and witnessed or if the patients had pure vertigo or isolated cranial nerve palsy.

On admission, neurologic deficit was assessed using the National Institutes of Health Stroke Scale (NIHSS).6 The NIHSS is a 42-point scale that quantifies neurologic deficit. Normal function without neurologic deficit is scored as zero, while complete hemiplegia with aphasia, gaze deviation, visual deficit, dysarthria, and sensory loss is given a score of 25, for example. Outcome at 3 months was determined using the NIHSS, Barthel index, and Rankin scale.7 The Barthel index (0-100) is a measure of the ability to perform activities of daily living such as eating, bathing, walking, and using the toilet. Patients able to perform all activities with complete independence are given a score of 100. The Rankin scale (0-5) is a simplified overall assessment of function in which a score of 0 indicates the absence of symptoms and a score of 5 indicates severe disability. To compare our results, patients were classified according to the criteria of the NINDS study.5 A score of 1 or less using the NIHSS criteria, 95 to 100 using the Barthel index, and 0 to 1 using the Rankin scale indicated no or minimal functional deficit. A score of 2 to 8 using the NIHSS criteria, 55 to 90 using the Barthel index, and 2 to 3 using the Rankin scale indicated mild or moderate functional deficit. A score of 9 or higher using the NIHSS criteria, 0 to 50 using the Barthel index, and 4 to 5 using the Rankin scale indicated severe functional deficit. "Favorable outcome" was defined as full independence (Barthel index of 100) or return to premorbid condition.

After obtaining informed consent from the patient or next of kin, 0.9 mg/kg of rtPA (alteplase [Actilyse, Thomae, Biberach, Germany]) was administered intravenously during a 60-minute period (10% bolus and 90% continuously). For early prevention of recurrent thrombosis and analogous to coronary thrombolysis, anticoagulation with heparin was routinely performed immediately after the end of rtPA infusion, aiming to increase activated partial thromboplastin time to 112 to 2 times the standard normal values.

Unenhanced computed tomographic (CT) scanning of the head was routinely performed on admission, 24 hours after admission, and whenever neurologic deterioration occurred. In some patients, follow-up magnetic resonance imaging, magnetic resonance angiography, or CT angiography was performed. Although transcranial Doppler ultrasonography was not routinely performed before treatment, it was performed within the first 24 hours.

Classification of stroke was based on the information available at discharge.

RESULTS

Twelve patients (9 men and 3 women) with typical, progressive brainstem symptoms were treated (Table 1). The mean (± SD) age was 63 ± 10 years (range, 41-78 years); the mean (± SD) interval between symptom onset and thrombolytic treatment was 134 ± 26 minutes (range, 100-175 minutes); and the mean (± SD) initial NIHSS score was 14 ± 11 points, with a median NIHSS score of 12 points (range, 4-37 points). Five patients had impairment of consciousness and hemiparesis or tetraparesis or decerebrate posturing, and 2 of these patients were comatose. In 6 patients, brainstem involvement could be demonstrated in the results of follow-up CT or magnetic resonance imaging.

In 1 patient (patient 10), basilar artery occlusion was documented in the results of transcranial Doppler ultrasonography before treatment.

Atherothrombosis was the most frequent cause (6 patients), and embolism was less frequent (2 patients). In 1 patient (patient 7), dissection of the vertebral artery was documented in the results of CT angiography; in 3 patients, the cause remained undetermined.

Excellent outcome with no or minimal functional deficit was reached in 7 patients. Of the 7, 4 patients had severe brainstem symptoms with impairment of consciousness on admission (patients 7, 8, 9, and 10); in 2 patients, brainstem infarction could be assessed in the results of follow-up magnetic resonance imaging. In 2 more patients (patients 1 and 2), the outcome was good with a score of 100 using the Barthel index, 2 using the Rankin scale, and mild neurologic sequelae (4 and 2 points, respectively, using the NIHSS criteria). In these patients, brainstem infarction was also documented. One patient (patient 4) showed considerable improvement: Neurologic deficit was minimal after 3 months (NIHSS, 1 point); however, the activities of daily living and grade of dependency were moderately impaired but comparable to the premorbid condition.

Taken together, a favorable outcome was reached in 10 of 12 consecutive patients.

In the remaining 2 patients (patients 11 and 12), the outcome was poor. A 65-year-old patient (patient 11) experienced a sudden onset of left-sided hemiparesis, followed by nausea and progressive loss of consciousness. On arrival at our hospital 90 minutes after symptom onset, he was comatose with decerebrate posturing. The results of cranial CT demonstrated a hyperdense basilar artery. Intravenous thrombolysis with 80 mg of rtPA was initiated 120 minutes after onset of symptoms; thrombolysis was effective. After 24 hours, his neurologic status was normal except for a moderate dysarthria. Three days later, the patient was found at 3 AM again unconscious and tetraplegic. The antithrombin III level was reduced to 69%, and the activated partial thromboplastin time was 41 seconds despite continuous infusion of 1300 U/h of heparin. Although the time of the onset of symptoms could not be assessed reliably, the patient was treated again with intravenous rtPA. However, the patient had a pontine infarction, and symptoms only gradually improved. The results of magnetic resonance angiography demonstrated a tight stenosis of the middle part of the basilar artery.

A 70-year-old patient (patient 12) was admitted 135 minutes after sudden onset of vertigo, dysarthria, and severe hemiparesis. Thrombolysis with 75 mg of rtPA was initiated 25 minutes later. However, the symptoms were progressive, and the patient became tetraparetic and comatose. The results of CT exhibited a small, non–space-occupying, parietal hemorrhage. The results of follow-up CT after 24 hours showed a large brainstem infarction and an increasing hemorrhage with mass effect. In the results of CT angiography, a high-grade stenosis of the distal basilar artery was documented. Brain death was diagnosed in this patient on day 5. This was the only patient with hemorrhagic transformation in the results of follow-up CT.

COMMENT

Vertebrobasilar ischemic stroke is different in many ways from stroke in the carotid axis. It is less frequent, its prognosis is worse, and atherosclerosis is the most frequent cause.2 Therefore, the transfer of therapeutic concepts from hemispheric to vertebrobasilar ischemic stroke is limited.4 Therapeutic trials especially designed for vertebrobasilar ischemic stroke are rare and mostly restricted to patients with angiography-proved basilar artery occlusion,810 although this pathologic characteristic is only found in about 14% of patients with vertebrobasilar ischemic stroke.2 The main therapeutic strategy tested is local intra-arterial thrombolysis. Even after successful recanalization, an approximate mortality rate of 50% has been reported.8 However, there are also occasional reports of benign outcome in angiography-proved basilar artery occlusion without thrombolytic therapy.11 The length of basilar artery obstruction, the state of the collaterals, and the clinical condition on admission were valuable prognostic factors. To our knowledge, no randomized, placebo-controlled trial of thrombolytic therapy in acute basilar artery occlusion has been conducted. The only larger studies conducted were those of Hacke and coworkers9 in 1988, Brandt and coworkers8 in 1996, and Zeumer and coworkers10 in 1993. Almost all patients were treated with intra-arterial thrombolysis within various time frames, some of them even later than 24 hours after symptom onset. However, intra-arterial thrombolysis is restricted to a few specialized centers that have angiography facilities and special teams available 24 hours a day. Furthermore, intra-arterial thrombolysis is a time-consuming procedure with a long "door-to-needle" time. As experimental data12 show, the duration of ischemia is a crucial factor for the success of therapeutic intervention. Furthermore, the symptoms of vertebrobasilar ischemic stroke are often fluctuating or progressive, sometimes leading to sudden deterioration. The better the clinical condition is on admission, the better the prognosis after thrombolysis.4 Therefore, should patients with acute symptoms of brainstem ischemia be treated immediately with intravenous rtPA within the 3-hour time frame as in the NINDS study5 or be transferred to specialized centers for intra-arterial thrombolysis?

Data on intravenous thrombolysis with rtPA in vertebrobasilar ischemic stroke are scarce. In a larger study, von Kummer and coworkers13 described 5 patients with angiography-proved basilar artery occlusion treated within 6 hours after symptom onset with 70 mg of rtPA intravenously. Because 3 patients died of extended brainstem infarction, 1 patient remained "locked in," and only 1 patient fully recovered, intravenous treatment was abandoned. Huemer and coworkers14 described 16 patients with acute occlusion of the basilar artery treated with intravenous rtPA within 6 hours after symptom onset. The results were more encouraging since recanalization was achieved in 10 patients. Herderscheé and coworkers15 described 2 patients with angiography-proved basilar artery occlusion treated with 100 mg of rtPA intravenously. One patient was successfully treated 130 minutes after symptom onset, and the other patient was treated after 6 hours and died from hemorrhagic infarction of the pons despite extensive collateralization. The difference in time interval was crucial; in our patient 11, treatment within 2 hours was effective whereas a second treatment, which was beyond the early time frame, was ineffective. Kamps and coworkers16 also described a patient with subtotal vertebrobasilar stenosis and rapidly progressive severe brainstem symptoms who was successfully treated twice within 1 week. However, a permanent therapeutic success could not be achieved.

Whether thrombolysis should be followed immediately by administration of heparin in patients with acute vertebrobasilar ischemic stroke is a question that cannot be answered from our limited data. On the one hand, there is a substantial risk of reocclusion after successful thrombolysis due to underlying atherosclerotic pathologic factors17 as demonstrated in our patient 11; on the other hand, the risk of severe hemorrhage as shown in our patient 12 might be increased.

Our data of favorable 3-month outcome in 10 of 12 consecutive patients treated within 3 hours after onset of typical brainstem symptoms suggest effectiveness of this treatment within the given time frame. Beyond that time frame, no conclusions can be drawn.

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Article Information

Accepted for publication December 1, 1997.

Reprints: Wolf-Dieter Heiss, MD, Department of Neurology, University Hospital of Cologne, Joseph-Stelzmann-Strasse 9, D-50924 Cologne, Germany.

References
1.
Turney  TMGarraway  WMWhisnant  JP The natural history of hemispheric and brainstem infarction in Rochester, Minnesota. Stroke. 1984;15790- 794Article
2.
Hornig  CRBüttner  THoffmann  ODorndorf  W Short-term prognosis of vertebrobasilar ischemic stroke. Cerebrovasc Dis. 1992;2273- 281Article
3.
Labauge  RPages  MMarty-Double  CBlard  JMBoukobza  MSalvaing  P Occlusion du tronc basilaire. Rev Neurol. 1981;10545- 571
4.
Becker  KJPurcell  LLHacke  WHanley  DF Vertebrobasilar thrombosis: diagnosis, management, and the use of intra-arterial thrombolytics. Crit Care Med. 1996;241729- 1742Article
5.
The National Institute of Neurological Disorders and Stroke r-tPA Stroke Study Group, Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;3331581- 1587Article
6.
Lyden  PBrott  TTilley  B  et al.  Improved reliability of the NIH Stroke Scale using video training. Stroke. 1994;252220- 2226Article
7.
van Swieten  JCKoudstaal  PJVisser  MCSchouten  HJAvan Gijn  J Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19604- 607Article
8.
Brandt  Tvon Kummer  RMüller-Küppers  MHacke  W Thrombolytic therapy of acute basilar artery occlusion. Stroke. 1996;27875- 881Article
9.
Hacke  WZeumer  HFerbert  ABrückmann  Hdel Zoppo  GJ Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke. 1988;191216- 1222Article
10.
Zeumer  HFreitag  HJZanella  FThie  AArning  C Local intra-arterial fibrinolytic therapy in patients with stroke: urokinase versus recombinant tissue plasminogen activator (rt-PA). Neuroradiology. 1993;35159- 162Article
11.
Brandt  TPessin  MSKwan  ESCaplan  LR Survival with basilar artery occlusion. Cerebrovasc Dis. 1995;5182- 187Article
12.
Heiss  WDRosner  G Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol. 1983;14294- 301Article
13.
von Kummer  RForsting  MSartor  KHacke  W Intravenous recombinant tissue plasminogen activator in acute stroke. Hacke  Wdel  Zoppo GJHirschberg  Meds.Thrombolytic Therapy in Acute Ischemic Stroke New York, NY Springer Publishing Co Inc1991;161- 167
14.
Huemer  MNiederwieser  VLadurner  G Thrombolytic treatment for acute occlusion of the basilar artery. J Neurol Neurosurg Psychiatry. 1995;58227- 228Article
15.
Herderscheé  DLimburg  MHijdra  AKoster  PA Recombinant tissue plasminogen activator in two patients with basilar artery occlusion. J Neurol Neurosurg Psychiatry. 1991;5471- 73Article
16.
Kamps  IWeiss  JRingelstein  EB Repetitive Behandlung einer subtotalen vertebrobasilären Stenose mit "tissue plasminogen activator" (tPA). Nervenarzt. 1992;63755- 760
17.
Becker  KJMonsein  LHUlatowski  JMirski  MWilliams  MHanley  DF Intraarterial thrombolysis in vertebrobasilar occlusion. AJNR Am J Neuroradiol. 1996;17255- 262
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