Bernd Eckert

Aggressive Therapy With Intravenous Abciximab and Intra-Arterial rtPA and Additional PTA/Stenting Improves Clinical Outcome in Acute Vertebrobasilar Occlusion Combined Local Fibrinolysis and Intravenous Abciximab in Acute Vertebrobasilar Stroke Treatment (FAST): Results of a Multicenter Study

Background and Purpose— A combined therapy of local recombinant tissue plasminogen activator (rtPA) fibrinolysis and intravenous Abciximab platelet inhibition with additional percutaneous transluminal angioplasty (PTA)/stenting may improve recanalization and neurological outcome in patients with acute vertebrobasilar occlusion. Methods Combined FAST therapy consisted on intravenous bolus of Abciximab (0.25 mg/kg) followed by a 12-hour infusion therapy (0.125 &mgr;g/kg per minute) and low-dose intra-arterial rtPA (median dosage: 20 mg, FAST cohort: N=47). The results were compared with a retrospective cohort, treated by intraarterial rtPA monotherapy (median dosage: 40 mg, rtPA cohort, N=41). Additional PTA/stenting was performed in case of severe residual stenosis. Recanalization success was classified according to the Trials in Myocardial Infarction (TIMI) criteria: TIMI0/1, failed recanalization; TIMI2/3, successful recanalization. Bleeding complications were evaluated according to severe extracerebral hemorrhage (ECH), asymptomatic intracerebral hemorrhage (AIH), and symptomatic intracerebral hemorrhage (SIH). Results— Overall bleeding rate was higher under the combined therapy, but the SIH rate did not differ (FAST versus rtPA: ECH, 3% versus 0%; AIH, 32% versus 22%; SIH 13% versus 12%). Additional PTA/stenting was performed in 14 (FAST) versus 5 (rtPA) patients. TIMI2/3 recanalization rate was similar (FAST, 72%; rtPA, 68%), but TIMI3 rate was remarkably higher under combined therapy (FAST, 45%; rtPA, N=22%). Neurologic outcome appeared better under combined therapy (FAST versus rtPA: favorable outcome rate: 34% versus 17%) with a significantly lower mortality rate (FAST versus rtPA: 38% versus 68%; P=0.006). These results were consistent for embolic and atherothrombotic occlusions. Conclusion Combined therapy of intravenous Abciximab and half dose intra-arterial rtPA with additional PTA/stenting appears to improve neurologic outcome in acute vertebrobasilar occlusion despite an increase of overall bleeding complications.

Endovascular therapy of acute vertebrobasilar occlusion: early treatment onset as the most important factor.

In view of the poor prognosis for patients with acute intracranial vertebrobasilar occlusion (VBO), factors were sought that predict survival and good neurologic outcome after acute endovascular treatment by means of local intra-arterial fibrinolysis (LIF) and percutaneous transluminal angioplasty (PTA). LIF was performed in 83 patients with angiographically established acute VBO. A significant residual stenosis after LIF was treated by additional PTA in 8 patients. The types of occlusion were classified as either embolic occlusion (EO) or atherothrombotic occlusion (AO). Outcome was evaluated after 3 months by the Barthel Index (BI) as favorable (BI >90), unfavorable (BI <90) or death and compared for each of 3 diagnostic or treatment variables: recanalization success, occlusion type and time to treatment. Four fibrinolytic treatment modes [urokinase, low-dose and high-dose recombinant tissue-type plasminogen activator (rt-PA), rt-PA + Lys-plasminogen] were also analyzed. The outcome was favorable in 19 patients (23%), unfavorable in 14 (17%) and 50 died (60%). Recanalization was successful in 54 patients (66%). The neurologic outcome was better in recanalized than in nonrecanalized patients (favorable outcome: 30 vs. 10%, mortality: 54 vs. 72%; p = 0.118). The neurologic outcome was better in EO than in AO (favorable outcome: 31 vs. 17%, mortality: 47 vs. 70%, p = 0.112). Under combined treatment by LIF and PTA in 8 patients with AO, 4 survived, 3 with a favorable outcome (38%). Early treatment onset (≤6 h) led to a significantly better neurologic outcome than delayed treatment onset (>6 h; favorable outcome: 36 vs. 7%, mortality: 52 vs. 70%, p = 0.005). Although no statistically significant differences were found between the types of fibrinolytic agents, treatment with rt-PA and Lys-plasminogen tended toward better results. Early treatment onset proved to be the most important factor for successful endovascular therapy in acute VBO, whereas recanalization and presence of an embolic occlusion also tended toward better results. Additional PTA may be a promising therapy in cases of significant residual stenosis after LIF.

The neurological syndrome in adults during the 2011 northern German E. coli serotype O104:H4 outbreak

The aim of this study was to describe the neurological syndrome in the largest cohort of adult patients with a complicated Shiga toxin-producing Escherichia coli infection. The recent outbreak of Shiga toxin-producing E. coli serotype O104:H4 in northern Germany affected more than 3842 patients, 22% of whom developed haemolytic uraemic syndrome. The proportion of adult patients was unusually high, and neurological complications were frequent and severe. In three hospitals, population-based evaluation of 217 patients with complicated Shiga toxin-producing E. coli infection was carried out, including neurological, neuroradiological, neurophysiological, cerebrospinal fluid and neuropathological analyses. Of the 217 patients with complicated Shiga toxin-producing E. coli infection, 104 (48%) developed neurological symptoms. Neurological symptoms occurred 5.3 days (mean) after first diarrhoea and 4 days after onset of haemolytic uraemic syndrome. Of the infected patients with neurological symptoms, 67.3% presented with cognitive impairment or aphasia. During the course of the disease, 20% of the patients developed epileptic seizures. The onset of neurological symptoms was paralleled by increases in blood urea nitrogen and serum creatinine. In 70 patients with cerebral magnetic resonance imaging, the most common findings were symmetrical hyperintensities in the region of abducens nucleus and lateral thalamus. On follow-up scans, these abnormalities were resolved. Neuropathological analysis revealed regionally accentuated astrogliosis and microgliosis, more predominant in the thalamus and brainstem than in the cortex, and neuronal expression of globotriaosylceramide. There were no signs of microbleeds, thrombotic vessel occlusion or ischaemic infarction. The neurological syndrome in adult patients with complicated Shiga toxin-producing E. coli infection is a rapidly progressive and potentially life-threatening disease necessitating intensive care unit treatment and intubation in >30% of cases. The outcome of neurological patients in the 2011 northern German Shiga toxin-producing E. coli O104:H4 outbreak was surprisingly good. Magnetic resonance imaging and neuropathological findings point to a mixed toxic and inflammatory pathomechanism leading to largely reversible damage of neuronal function.

Local Intra-Arterial Fibrinolysis in Acute Hemispheric Stroke: Effect of Occlusion Type and Fibrinolytic Agent on Recanalization Success and Neurological Outcome

Background: To evaluate the effect of occlusion type and fibrinolytic agent on recanalization success and clinical outcome in patients undergoing local intra-arterial fibrinolysis (LIF) in acute hemispheric stroke. Methods: LIF was performed in 137 patients with angiographically established occlusion in the carotid circulation within 6 h of stroke onset. Retrospective analysis included recanalization success, recanalization time, type of occlusion and fibrinolytic treatment mode. Five types of occlusion were categorized: intracranial bifurcation (carotid ‘T’) of the internal carotid artery (ICA; n = 35); proximal segment of the middle cerebral artery (MCA; n = 66); distal segment of the MCA (n = 20); extracranial ICA with MCA embolism (n = 8); multiple peripheral branches of the anterior cerebral artery and the MCA (n = 8). Neurologic outcome was evaluated after 3 months by Barthel Index (BI) as good (BI >90), moderate (BI 50–90), poor (BI <50) or death. Results: Recanalization was achieved in 74 patients (54%). Mean recanalization time in recanalized patients was 91 min. Neurologic outcome was good in 48 patients (35%), moderate in 34 (25%), poor in 30 (22%) and 25 died (18%). Outcome was significantly better in recanalized than in nonrecanalized patients (p < 0.001). Treatment results were significantly better in proximal and distal MCA occlusion than in carotid ‘T’ occlusions (p < 0.001). Recanalization success hardly differed between urokinase and rt-PA. Combined treatment with rt-PA and lys-plasminogen tended toward a faster recanalization. Parenchymal hemorrhage occurred in 13 patients (9%). Conclusion: The type of occlusion is of high prognostic value for successful fibrinolysis in the anterior circulation. However, recanalization is a time-consuming process even with an intra-arterial approach. Recanalization did not differ between type or dosage of plasminogen activators. Further innovative attempts are warranted towards hastening recanalization time in endovascular acute stroke treatment.

Cerebral Blood Flow Predicts Lesion Growth in Acute Stroke Patients

Background and Purpose— We sought to study the role of MRI-derived cerebral blood flow (CBF) measurements for the prediction of lesion development in acute stroke patients. Methods— Thirty-two patients were treated with tissue plasminogen activator. Diffusion-weighted (DWI) and perfusion-weighted MRI, T2-weighted imaging, and MR angiography were performed before treatment (2.8±0.9 hours after symptom onset) and on follow-up (days 1 and 7). CBF thresholds (12 and 22 mL/100 g per minute) were applied to bolus tracking MRI maps to determine predictive cutoff levels. Results— In 21 patients (group A), the terminal lesion volume (T2-weighted imaging) was larger than the initial DWI lesion volume (89±93 versus 21±38 mL). In 11 patients (group B), the terminal lesion volume was smaller than the initial DWI lesion volume (7±27 versus 15±29 mL). The initial DWI lesion volume did not differ between both groups. The presence of a tissue volume ≥50 mL with a CBF value ≤12 mL/100 g per minute was predictive for lesion enlargement to day 7 in T2-weighted imaging (positive predictive value, 0.80). Conclusions— The presence of a tissue volume ≥50 mL with a CBF value ≤12 mL/100 g per minute predicts further lesion growth in hyperacute stroke patients. MRI-derived CBF values, with all their present limitations, are valuable in early estimation of prognosis of stroke patients.

Editorial Comment—Carotid Artery Stenting With or Without Protection Devices? Strong Opinions, Poor Evidence!

In recent years, endovascular treatment of carotid artery stenosis has profited from substantial technical improvements, but the dominant point of discussion circles around the so-called cerebral protection devices. In this issue of Stroke , Cremonesi et al1 report their impressive single-center experience with protected carotid artery stenting (CAS) in 442 patients. The overall complication rate was 3.4%, and the 30-day ipsilateral stroke/death rate was 1.1%. The authors conclude that protection devices are feasible and effective in preventing distal embolization. In a recent Stroke issue, Kastrup et al,2 who systematically reviewed single-center CAS studies, concluded that protection devices appear to reduce thromboembolic complications during CAS. The appearance of debris during CAS and carotid endarterectomy (CEA) is a common event.3,4 At first glance, it seems reasonable to apply protection systems to catch particles by means of occlusive balloon systems or filtration baskets in the internal carotid artery. The beneficial use of such devices seems to be supported by a growing number of publications, mostly from the field of cardiology, reporting declining neurological complication rates. Despite the lack of further controlled studies, the use of protection devices has even become obligatory in the CREST (United States)5 and EVA3S (France) trials testing for equivalence of CAS and CEA. Paradoxically, some neuroradiologists continue to successfully perform CAS without protection devices …

Acute Basilar Artery Occlusion Treated With Combined Intravenous Abciximab and Intra-arterial Tissue Plasminogen Activator Report of 3 Cases

Background— Acute vertebrobasilar occlusion remains a disease with a high mortality even after treatment by local intra-arterial fibrinolysis. Adjunctive treatment with platelet glycoprotein IIb/IIIa receptor inhibitors such as abciximab may facilitate recanalization and improve the neurological outcome. Results after treatment of 3 patients by combined intravenous abciximab and local intra-arterial tissue plasminogen activator (tPA) are reported. Case Descriptions— Treatment was performed within 6 hours of stroke onset. Angiography revealed embolic occlusion of the basilar artery in 2 patients and atherothrombotic occlusion at the vertebrobasilar junction in 1 patient. Therapy consisted of intravenous abciximab bolus administration (0.25 mg/kg) followed by 12-hour infusion therapy (0.125 &mgr;g/kg per minute) and local intra-arterial thrombolysis with tPA (10 mg/h). Heparin was only applied for catheter flushing (500 IU/h). The patient with the atherothrombotic occlusion was treated with additional percutaneous transluminal angioplasty and stenting. Complete recanalization of the basilar artery occurred in 2 patients, whose conditions improved clinically to functional independence. In the third patient only partial recanalization was seen, with only slight clinical improvement. This patient died of cardiac failure 2 months later. Besides a subtle subarachnoid hemorrhage (n=1), no intracranial or extracranial bleeding complication was observed. Conclusions— The combination of glycoprotein IIb/IIIa receptor inhibitor with local intra-arterial tPA might be a promising therapy for patients with acute vertebrobasilar occlusion. Further studies are necessary to define the clinical benefit and the bleeding rate of this new pharmacological approach.

In-Hospital Complication Rates After Stent Treatment of 388 Symptomatic Intracranial Stenoses Results From the INTRASTENT Multicentric Registry

Background and Purpose— Stenting is increasingly used as an adjunct to medical therapy in symptomatic intracranial stenoses. High periprocedural adverse event rates are one of the limitations of endovascular treatment. Data from the INTRASTENT multicentric registry should demonstrate in-hospital complications at the current stage of clinical development of the stent procedure. Methods— Participating centers entered the records of all their consecutive intracranial stent procedures into the database. To determine the clinical outcome in the acute phase, we distinguished transient ischemic attack/nondisabling stroke (modified Rankin Scale <2), disabling stroke, death, and intracranial hemorrhage as clinical complications and analyzed whether they were associated with patient- or stenosis-related risk factors. Results— Data from 372 patients with 388 stenoses proved 4.8% disabling strokes and 2.2% deaths. Transient or minor events were detected in 5.4% of the cases. Hemorrhagic events (3.5%) occurred more frequently after treatment of middle cerebral artery stenoses (P=0.004) and were associated with significantly higher morbidity and mortality rates. Ischemic strokes by compromise of perforating branches were detected mainly in the posterior circulation. However, the overall rate of severe adverse events was not dependent from location, degree, and morphology of the stenosis or from patients age, gender, vascular risk factors, or type of qualifying event. Conclusion— The complication rates within the registry are within the limits of previously published data. Severe adverse events were equally distributed between potential risk groups with similar rates but different types of main complications in the anterior and posterior circulation.

Neuroprotection as Initial Therapy in Acute Stroke

Although a considerable body of scientific data is now available on neuroprotection in acute ischaemic stroke, this field is not yet established in clinical practice. At its third meeting, the European Ad Hoc Consensus Group considered the potential for neuroprotection in acute stroke and the practical problems attendant on the existence of a very limited therapeutic window before irreversible brain damage occurs, and came to the following conclusions. Neuroprotectants in Clinical Development: Convincing clinical evidence for an efficacious neuroprotective treatment in acute stroke is still required. Caution should be exercised in interpreting and extrapolating experimental results to stroke patients, who are a very heterogeneous group. The limitations of the time windows and the outcome measures chosen in trials of acute stroke therapy have an important influence on the results. The overall distribution of functional outcomes provides more statistical information than the proportion above a threshold outcome value. Neurological outcome should also be assessed. Neuroprotectants should not be tested clinically in phase II or phase III trials in a time window that exceeds those determined in experimental studies. The harmful effects of a drug in humans may override its neuroprotective potential determined in animals. Agents that act at several different levels in the ischaemic cascade may be more effective than those with a single mechanism of action. Current In-Hospital Management of Acute Stroke: The four major physiological variables that must be monitored and managed are blood pressure, arterial blood gas levels, body temperature, and glycaemia. The effects of controlling these physiological variables have not been studied in prospective trials, though they may all contribute to the outcome of acute ischaemic stroke and affect the duration of the therapeutic window. Optimal physiological parameters are inherently neuroprotective. Trials of new agents for the treatment of acute stroke should aim to maintain these physiological variables as close to normal as possible, and certainly within strictly defined limits. The Place of Neuroprotectants in Acute Stroke Management: Stroke patients are a very heterogeneous group with respect to stroke mechanisms and severity, general condition, age and co-morbidities. At the present time, the only firm guideline than can be proposed for patient selection is the need for early admission to enable neuroprotectant and/or thrombolytic treatment to be started as soon as possible within the therapeutic window. The severity of potential side-effects will largely determine who should assess a patient with suspected stroke and initiate treatment. There is little information on which to base the duration of neuroprotectant therapy, and more experimental data are needed. Even if prehospital treatment proves to be feasible, it should not replace comprehensive stroke management in a specialist hospital unit. Clinical trials of neuroprotectants should only be performed in stroke units. The combined approach of restoring blood flow and providing neuroprotection may be the most productive in human stroke, but current clinical trial design will have to change in order to test combination therapy. Important side-effects are those that interfere with any possible benefit or increase mortality. Pharmaco-Economic Aspects of Neuroprotectants: The early increase in hospital costs associated with neuroprotectant therapy may be balanced by the shorter length of hospital stay and lesser degree of disability of the surviving patients. The overall direct financial cost is highly dependent on the number of patients eligible for neuroprotectant therapy, which is itself dependent on the length of the therapeutic window and the severity of potential side-effects. A treatment that achieves a good functional outcome is the most cost-effective approach.

Transcranial Doppler Sonographic monitoring during percutaneous transluminal angioplasty of the internal carotid artery.

Abstract Our purpose was to assess the haemodynamic changes in the ipsilateral middle cerebral artery (MCA) during and after percutaneous transluminal angioplasty (PTA) of the internal carotid artery (ICA), and to compare them with clinical and angiographic findings. Transcranial Doppler Sonographic monitoring (TCD) of the MCA was performed during PTA in 22 patients with symptomatic severe stenosis of the ICA. Mean blood flow velocity (MBFV) and pulsatility index (PI) were recorded. During PTA, MBFV fell from 41 ± 15 cm/s to 23 ± 11 cm/s (P = 0.0001). Changes in PI were inconsistent. With reduction of MBFV of 50 % or less (in 10 cases) no complication occurred. With a reduction of more than 50 % (in 12), 6 patients developed neurological disturbances (transient ischaemic attacks in 5 and minor stroke in 1). This difference was significant (P = 0.0152). Symptomatic patients also had a higher rate of stroke prior to PTA (4/6) than patients who remained asymptomatic during PTA (0/6). After PTA had been performed MBFV and PI improved significantly (P = 0.0001), MBFV increasing to 48 ± 16 cm/s and PI from 0.64 ± 0.11 to 0.86 ± 0.15. TCD changes proved more sensitive to cerebral haemodynamics than angiography in 8 patients.