Arno Reich

Feasibility of Prehospital Teleconsultation in Acute Stroke – A Pilot Study in Clinical Routine

Background Inter-hospital teleconsultation improves stroke care. To transfer this concept into the emergency medical service (EMS), the feasibility and effects of prehospital teleconsultation were investigated. Methodology/Principal Findings Teleconsultation enabling audio communication, real-time video streaming, vital data and still picture transmission was conducted between an ambulance and a teleconsultation center. Pre-notification of the hospital was carried out with a 14-item stroke history checklist via e-mail-to-fax. Beside technical assessments possible influences on prehospital and initial in-hospital time intervals, prehospital diagnostic accuracy and the transfer of stroke specific data were investigated by comparing telemedically assisted prehospital care (telemedicine group) with local regular EMS care (control group). All prehospital stroke patients over a 5-month period were included during weekdays (7.30 a.m. –4.00 p.m.). In 3 of 18 missions partial dropouts of the system occurred; neurological co-evaluation via video transmission was conducted in 12 cases. The stroke checklist was transmitted in 14 cases (78%). Telemedicine group (n = 18) vs. control group (n = 47): Prehospital time intervals were comparable, but in both groups the door to brain imaging times were longer than recommended (median 59.5 vs. 57.5 min, p = 0.6447). The prehospital stroke diagnosis was confirmed in 61% vs. 67%, p = 0.8451. Medians of 14 (IQR 9) vs. 5 (IQR 2) stroke specific items were transferred in written form to the in-hospital setting, p<0.0001. In 3 of 10 vs. 5 of 27 patients with cerebral ischemia thrombolytics were administered, p = 0.655. Conclusions Teleconsultation was feasible but technical performance and reliability have to be improved. The approach led to better stroke specific information; however, a superiority over regular EMS care was not found and in-hospital time intervals were unacceptably long in both groups. The feasibility of prehospital tele-stroke consultation has future potential to improve emergency care especially when no highly trained personnel are on-scene. Trial Registration International Standard Randomised Controlled Trial Number Register (ISRCTN) ISRCTN83270177 83270177.

Alternate-Form Reliability of the Montreal Cognitive Assessment Screening Test in a Clinical Setting

Aims: The Montreal Cognitive Assessment (MoCA) has gained recognition for its validity in detecting cognitive impairment in several clinical populations. For serial assessments, alternate forms are needed to overcome possible practice effects. Our objective was to investigate the reliability of two German MoCA alternate forms for longitudinal assessment applications. Methods: The original and one of two alternate forms of the MoCA were administered within a 60-min interval of a clinical interview in a counterbalanced order to 100 healthy elderly controls, 30 patients with mild cognitive impairment (MCI) and 30 patients with Alzheimer’s disease (AD). The diagnosis of the majority of patients was supported by in vivo AD pathology biomarkers. Results: There was a strong correlation between the alternate forms and the original MoCA in all groups, but particularly in the clinical samples. Total mean scores did not differ significantly between the MoCA versions, even taking into account the presentation order. As in previous studies, age and education influenced performance in the MoCA. The same pattern of group differences (controls > MCI > AD) was observed for each of the versions. Conclusion: All three forms can be reliably and interchangeably used in serial cognitive assessment, confirming the MoCA’s applicability in research and clinical longitudinal approaches.

Fas/CD95 Regulatory Protein Faim2 Is Neuroprotective after Transient Brain Ischemia

Death receptor (DR) signaling has a major impact on the outcome of numerous neurological diseases, including ischemic stroke. DRs mediate not only cell death signals, but also proinflammatory responses and cell proliferation. Identification of regulatory proteins that control the switch between apoptotic and alternative DR signaling opens new therapeutic opportunities. Fas apoptotic inhibitory molecule 2 (Faim2) is an evolutionary conserved, neuron-specific inhibitor of Fas/CD95-mediated apoptosis. To investigate its role during development and in disease models, we generated Faim2-deficient mice. The ubiquitous null mutation displayed a viable and fertile phenotype without overt deficiencies. However, lack of Faim2 caused an increase in susceptibility to combined oxygen–glucose deprivation in primary neurons in vitro as well as in caspase-associated cell death, stroke volume, and neurological impairment after cerebral ischemia in vivo. These processes were rescued by lentiviral Faim2 gene transfer. In summary, we provide evidence that Faim2 is a novel neuroprotective molecule in the context of cerebral ischemia.

Collateral Vessels in Proximal Middle Cerebral Artery Occlusion: The ENDOSTROKE Study

PURPOSE To determine the impact of collateral vessel status on clinical and imaging outcomes in patients undergoing endovascular therapy (EVT) for proximal middle cerebral artery (MCA) occlusion. MATERIALS AND METHODS There were 160 patients with proximal MCA occlusion at six centers in this institutional review board-approved multicenter EVT registry. Angiograms were analyzed at a blinded core laboratory, and collateral vessel status was assessed by using the American Society of Interventional and Therapeutic Neuroradiology (ASITN)/Society of Interventional Radiology (SIR) collateral vessel grading system, while reperfusion was assessed by using the Thrombolysis in Cerebral Infarction (TICI) scale. Good outcome was defined as a modified Rankin Scale score of 0-2 at follow-up. Binary logistic regression analysis was performed by using parameters with P < .2 in univariate analysis. RESULTS Good clinical outcome was attained in 62 (39%) of the 160 patients, and TICI 2b-3 reperfusion was achieved in 94 (59%) patients. Nineteen patients had ASITN/SIR collateral vessel grades of 0 or 1, 63 patients had a grade of 2, and 78 patients had grades of 3 or 4. Better collateral vessels were associated with higher reperfusion rates (21%, 48%, and 77% for ASITN/SIR grades of 0 or 1, 2, and 3 or 4, respectively; P < .001), a higher proportion of infarcts smaller than one-third of the MCA territory (32%, 48%, and 69% for ASITN/SIR grades of 0 or 1, 2, and 3 or 4, respectively; P < .001), and a higher proportion of good clinical outcome (11%, 35%, and 49% for ASITN/SIR grades of 0 or 1, 2, and 3 or 4, respectively; P = .007). At multivariable analysis, collateral vessel status independently predicted reperfusion, final infarct size, and clinical outcome. Within an onset-to-treatment time (OTT) of 0-3 hours, collateral vessel status predicted final infarct size and reperfusion. Within an OTT of 3-6 hours, it additionally predicted clinical outcome, with 53% of patients with ASITN/SIR grades of 3 or 4 having a good outcome, as compared with 0% of patients with grades of 0 or 1 and 27% of patients with a grade of 2 (P = .008). CONCLUSION In this patient population, collateral vessel status independently predicted the pivotal outcome parameters of reperfusion, infarct size, and clinical outcome. These data underscore the utility of patient selection for EVT on the basis of collateral vessel status.

Modulation of β-amyloid by a single dose of GSK933776 in patients with mild Alzheimer’s disease: a phase I study

IntroductionIn this study, we evaluated the safety and pharmacodynamic effects of the Fc-inactivated anti-β-amyloid (anti-Aβ) monoclonal antibody GSK933776 in patients with mild Alzheimer’s disease and mild cognitive impairment. Aβ and tau levels were investigated in cerebrospinal fluid (CSF), and the relationship between Aβ levels and Aβ modulation in plasma was explored. The feasibility of a continuous sampling method using a lumbar catheter was assessed.MethodsThis trial was a phase I, open-label, uncontrolled, single-dose, exploratory experimental medicine study of intravenous GSK933776 at doses of 1 mg/kg, 3 mg/kg or 6 mg/kg (n = 6/group). The time course of plasma and CSF concentrations of GSK933776 and Aβ was assessed. Sample size was based on feasibility, and no formal statistical analyses were performed.ResultsFollowing administration of GSK933776 at doses of 1 mg/kg, 3 mg/kg and 6 mg/kg, there were decreases from baseline in CSF Aβ1–42 (from 0 to 12 hours) by 22.8 pg/ml (6.2%), 43.5 pg/ml (9.2%) and 60.5 pg/ml (12.5%), respectively. Plasma concentrations of total Aβ18–35 and Aβ4228–42 increased immediately after infusion and CSF tau concentration increased slightly, but did not significantly change, following administration of all doses of GSK933776. Pharmacokinetics confirmed the presence of GSK933776 in the CSF, which exhibited a dose–response relationship. One patient underwent minor surgery without sequelae following a ruptured lumbar catheter.ConclusionGSK933776 demonstrated pharmacological activity and target engagement in CSF and plasma, and the continuous sampling method via a catheter successfully assessed the Aβ changes following single-dose administration of GSK933776.Trial registrationClinicalTrials.gov Identifier: NCT01424436. Registered 4 August 2011

Evidence of the Sensitivity of the MoCA Alternate Forms in Monitoring Cognitive Change in Early Alzheimer's Disease

Background/Aims: There is an increasing interest in using the Montreal Cognitive Assessment (MoCA) test as a monitoring tool in Alzheimers disease (AD) in both research and clinical settings. Our aim was to investigate the utility of alternate forms of the MoCA in detecting cognitive deterioration in a sample of early AD patients followed longitudinally in an outpatient memory clinic. Method: Twenty-five patients with early-stage AD (prodromal or mild dementia) were administered the original version and one of two previously validated alternate forms of the MoCA within an interval of about 1 year. The decline over time and the rate of change of the MoCA were compared to the total score of a standardized neuropsychological assessment battery (Consortium to Establish a Registry of Alzheimers Disease; CERAD-Plus). Responsiveness to change was determined by calculating standard response means and the respective effect sizes. Results: Sixty percent of the sample showed a clinical decline on the clinical dementia rating (CDR) scale. There was significant deterioration in the MoCA and CERAD total scores. Conclusion: The results demonstrate that the MoCA is capable of detecting change over time and seems to be a valid tool with small to moderate sensitivity for monitoring cognitive change in early AD.

Stimulation of Toll-like receptor 9 by chronic intraventricular unmethylated cytosine-guanine DNA infusion causes neuroinflammation and impaired spatial memory.

Bacterial DNA contains a high frequency of unmethylated cytosine-guanine (CpG) motifs that have strong immunostimulatory properties; they are recognized by mammalian Toll-like receptor 9 (TLR9). Because accumulating data suggest that chronic inflammatory processes are involved in the pathogenesis of neurodegenerative diseases, we hypothesized that inflammatory responses stimulated by CpG DNA might contribute to neurodegeneration and brain dysfunction. To assess the effects of continuous CpG DNA exposure in the brain, C57BL/6 (n = 21) and TLR9-deficient mice (n = 15) were given intracerebroventricular infusions of CpG DNA or saline for 28 days. Spatial memory assessed weekly by Morris water maze demonstrated impairment in CpG-treated wild-type mice but not in TLR9-deficient or control-treated mice. Motor function was not affected. Immunohistochemical analysis revealed marked microglial activation and acute axonal damage surrounding the ventricles, ependymal disruption, and reactive astrogliosis within the hippocampal formation in the CpG-treated wild-type but not TLR9-deficient mice or saline-infused controls. These results suggest that the unfavorable effects of CpG DNA are dependent on TLR9 signaling and that exposure to bacterial DNA may contribute to impaired neural function, neuroinflammation, and subsequent neurodegeneration.

Stent Retriever Thrombectomy in Patients Who Are Ineligible for Intravenous Thrombolysis: A Multicenter Retrospective Observational Study

BACKGROUND AND PURPOSE: Intravenous thrombolysis with rtPA is the standard of care for patients with acute ischemic stroke within 4.5 hours after symptom onset. However, a considerable number of patients are ineligible for IV thrombolysis due to various contraindications. Recent studies have proved the superiority of mechanical thrombectomy for patients with large-vessel occlusions in combination with IV rtPA compared with IV rtPA alone. We aimed to demonstrate the efficacy of mechanical thrombectomy for patients who are ineligible for IV rtPA. MATERIALS AND METHODS: Patients from the stroke registries of 4 dedicated centers who were treated with mechanical thrombectomy from January 2010 to October 2014 were retrospectively evaluated. Inclusion criteria were the following: acute stroke due to proved large-artery occlusion, ineligibility for IV thrombolysis, and a timeframe of ≤4.5 hours between stroke and the start of mechanical thrombectomy. Recanalization success, periprocedural complications, clinical outcome, and hemorrhages were evaluated. RESULTS: One hundred thirty endovascular recanalization procedures were identified. The locations were the following: proximal ICA in 17 (13.1%), terminus ICA in 25 (19.2%), M1 segment in 77 (59.2%), and M2 segment in 11 (8.5%). TICI 2b/3 results were achieved in 101 (77.7%), and an mRS score of 0–2 in 47 patients (37.9%). There was a significant correlation between TICI 2b/3 results and good clinical outcomes (87.2% versus 6.8%; P = .048). A good clinical result was most frequent when recanalization was achieved within 4.5 hours (37/74 = 50% versus 10/50 = 20.0%; P = .001). Symptomatic hemorrhage occurred in 13.1% of patients; mortality was 24.2%. Periprocedural complications were recorded in 10 patients (7.7%). CONCLUSIONS: Mechanical thrombectomy can achieve good clinical outcomes in patients with acute large-artery occlusion ineligible for IV thrombolysis, in particular when recanalization is reached early.

Active push deployment technique improves stent/vessel-wall interaction in endovascular treatment of acute stroke with stent retrievers.

Background The optimal interaction between stent struts and thrombus is crucial for successful revascularization in endovascular stroke therapy with stent retrievers. Deploying the stent retriever by actively pushing it into the thrombus increases the radial force with which the stent struts expand into the thrombus. Objective To examine the active push deployment (APD) technique in an in vitro model and present our clinical experience with this technique. Methods In an in vitro experiment we investigated the configuration of a Solitaire and a Trevo ProVue device (both 4×20 mm), depending on whether the devices were deployed using the APD technique or simple unsheathing. We retrospectively assessed the effectiveness and safety of this technique by analyzing 130 patients with large vessel occlusions (carotid T or M1 segment of the middle cerebral artery), who received endovascular treatment with a Trevo device (4×20 mm) that was deployed using the APD technique. Results In vitro experiment: the APD technique improved apposition of the devices to the vessel wall. There was widening of 30% (Trevo) and 19% (Solitaire) at the cost of a shortening of 5% and 4%, respectively, when the devices were deployed in a carotid T model. Clinical study: the revascularization rate (Thrombolysis in Cerebral Infarction ≥2b) with the Trevo device was 90%. There were no retriever-associated dissections or perforations in 278 retrieval maneuvers. Conclusions The APD technique improves apposition of the tested devices to the vessel wall. The widening effect comes at the cost of minimal shortening of the devices. Our clinical experience shows that using the APD technique to deploy the Trevo device is effective and safe.

Optimizing endovascular stroke treatment: removing the microcatheter before clot retrieval with stent-retrievers increases aspiration flow.

Background Flow control during endovascular stroke treatment with stent-retrievers is crucial for successful revascularization. The standard technique recommended by stent-retriever manufacturers implies obstruction of the respective access catheter by the microcatheter, through which the stent-retriever is delivered. This, in turn, results in reduced aspiration during thrombectomy. In order to maximize aspiration, we fully retract the microcatheter out of the access catheter before thrombectomy—an approach we term the ‘bare wire thrombectomy’ (BWT) technique. We verified the improved throughput with systematic in vitro studies and assessed the clinical effectiveness and safety of this method. Methods We compared aspiration flow of water through various access catheters (5–8 F) with a Rebar microcatheter (0.18 inch and 0.27 inch) and a Trevo stent-retriever using the standard technique and the BWT technique in vitro. We also retrospectively analyzed 302 retrieval maneuvers in 117 patients who received endovascular treatment with a stent-retriever between February 2010 and April 2015. Results In the in vitro experiment, removal of the microcatheter in all tested settings resulted in significantly increased aspiration flow through the access catheter (p<0.001). This effect was particularly pronounced in access catheters with a diameter of ≤7 F. In the clinical study, the revascularization rate (Thrombolysis In Cerebral Infarction ≥2b) was 91%. There were no complications associated with the BWT technique in 302 retrieval maneuvers. Conclusions The BWT technique results in improved aspiration flow rates compared with the standard deployment technique. Our clinical data show that the BWT technique is effective and safe.