Sandra Boy

Amyloid-β Contributes to Blood–Brain Barrier Leakage in Transgenic Human Amyloid Precursor Protein Mice and in Humans With Cerebral Amyloid Angiopathy

Background and Purpose— Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-&bgr; (A&bgr;) deposition in the blood–brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to A&bgr; compromising the BBB. Methods— We characterized 19 patients with acute stroke with “probable CAA” for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of A&bgr; on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. Results— Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. A&bgr;40 decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. Conclusions— Our findings indicate that A&bgr; contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that A&bgr; causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.

TeleStroke Units Serving as a Model of Care in Rural Areas: 10-Year Experience of the TeleMedical Project for Integrative Stroke Care

Background and Purpose— Stroke Unit care improves stroke prognosis and is recommended for all patients with stroke. In rural areas, population-wide implementation of Stroke Units is challenging. Therefore, the TeleMedical Project for integrative Stroke Care (TEMPiS) was established in 2003 as a TeleStroke Unit network to overcome this barrier in Southeast Bavaria/Germany. Evaluation of its implementation between 2003 and 2005 had revealed improved process quality and clinical outcomes compared with matched hospitals without TeleStroke Units. Data on sustainability of these effects are lacking. Methods— Effects on the stroke care of the local population were analyzed by using data from official hospital reports. Prospective registries from 2003 to 2012 describe processes and outcomes of consecutive patients with stroke and transient ischemic attack treated in TEMPiS hospitals. Quality indicators assess diagnostics, treatment, and outcome. Rates and timeliness of intravenous thrombolysis as well as data on teleconsultations and secondary interhospital transfers were reported over time. Results— Within the covered area, network implementation increased the number of patients with stroke and transient ischemic attack treated in hospitals with (Tele-)Stroke Units substantially from 19% to 78%. Between February 2003 and December 2012, 54 804 strokes and transient ischemic attacks were treated in 15 regional hospitals, and 31 864 teleconsultations were performed. Intravenous thrombolysis was applied 3331 stroke cases with proportions increasing from 2.6% to 15.5% of all patients with ischemic stroke. Median onset-to-treatment times decreased from 150 (interquartile range, 127–163) to 120 minutes (interquartile range, 90–160) and door-to-needle times from 80 (interquartile range, 68–101) to 40 minutes (interquartile range, 29–59). Conclusions— TeleStroke Units can provide sustained high-quality stroke care in rural areas.

Transcranial Ultrasound from Diagnosis to Early Stroke Treatment – Part 2: Prehospital Neurosonography in Patients with Acute Stroke – The Regensburg Stroke Mobile Project

Background and Purpose: The primary aim of this study was to investigate the diagnostic accuracy and time frames for neurological and transcranial color-coded sonography (TCCS) assessments in a prehospital ‘911’ emergency stroke situation by using portable duplex ultrasound devices to visualize the bilateral middle cerebral arteries (MCAs). Methods: This study was conducted between May 2010 and January 2011. Patients who had sustained strokes in the city of Regensburg and the surrounding area in Bavaria, Germany, were enrolled in the study. After a ‘911 stroke code’ call had been dispatched, stroke neurologists with expertise in ultrasonography rendezvoused with the paramedic team at the site of the emergency. After a brief neurological assessment had been completed, the patients underwent TCCS with optional administration of an ultrasound contrast agent in cases of insufficient temporal bone windows or if the agent had acute therapeutic relevance. The ultrasound studies were performed at the site of the emergency or in the ambulance during patient transport to the admitting hospital. Relevant timelines, such as the time from the stroke alarm to patient arrival at the hospital and the duration of the TCCS, were documented, and positive and negative predictive values for the diagnosis of major MCA occlusion were assessed. Results: A total of 113 patients were enrolled in the study. MCA occlusion was diagnosed in 10 patients. In 9 of these 10 patients, MCA occlusion could be visualized using contrast-enhanced or non-contrast-enhanced TCCS during patient transport and was later confirmed using computed tomography or magnetic resonance angiography. One MCA occlusion was missed by TCCS and 1 atypical hemorrhage was misdiagnosed. Overall, the sensitivity of a ‘field diagnosis’ of MCA occlusion was 90% [95% confidence interval (CI) 55.5–99.75%] and the specificity was 98% (95% CI 92.89–99.97%). The positive predictive value was 90% (95% CI 55.5–99.75%) and the negative predictive value was 98% (95% CI 92.89–99.97%). The mean time (standard deviation) from ambulance dispatch to arrival at the patient was 12.3 min (7.09); the mean time for the TCCS examination was 5.6 min (2.2); and the overall mean transport time to the hospital was 53 min (18). Conclusion: Prehospital diagnosis of MCA occlusion in stroke patients is feasible using portable duplex ultrasonography with or without administration of a microbubble contrast agent. Prehospital neurological as well as transcranial vascular assessments during patient transport can be performed by a trained neurologist with high sensitivity and specificity, perhaps opening an additional therapeutic window for sonothrombolysis or neuroprotective strategies.

Transcranial Ultrasound from Diagnosis to Early Stroke Treatment

Background: To test whether portable duplex ultrasound devices can be used in a prehospital ‘911’ emergency situation to assess intracranial arteries. Methods: Non-contrast-enhanced transcranial duplex ultrasound studies were performed either immediately at the site of the emergency (i.e. private home) or after transfer into the emergency helicopter/ambulance vehicle. Results: A total of 25 patients were enrolled. In 5/25 cases, intracranial vessels could not be visualized due to insufficient quality of the temporal bone window. In 20/25 cases, bilateral visualization and Doppler flow measurements of the middle cerebral artery could be assessed in a mean time less than 2 min. Conclusion: Emergency assessment of intracranial arteries using portable duplex ultrasound devices is feasible shortly after arrival at the patient’s site.

Is Mobile Teleconsulting Equivalent to Hospital-Based Telestroke Services?

Background and Purpose— Telemedicine is increasingly used to provide acute stroke expertise for hospitals without full-time neurological services. Teleconsulting through mobile laptop computers may offer more flexibility compared with hospital-based services, but concerns about quality and technical reliability remain. Methods— We conducted a controlled trial, allocating hospital-based or mobile teleconsulting in a shift-by-shift sequence and evaluating technical parameters, acceptability, and impact on immediate clinical decisions. Both types of telemedicine workstations were equipped with DICOM (Digital-Imaging-and-Communications-in-Medicine) viewer and videoconference software. The laptop connected by asymmetrical broadband UMTS (Universal-Mobile-Telecommunication-Systems) technology with a one-way spoke-to-hub video transmission, whereas the hospital-based device used landline symmetrical telecommunication, including a 2-way videoconference. Results— One hundred twenty-seven hospital-based and 96 mobile teleconsultations were conducted within 2 months without any technical breakdown. The rates per allocated time were similar with 3.8 and 4.0 per day. No significant differences were found for durations of videoconference (mean: 11±3 versus 10±3 minutes, P=0.07), DICOM download (3±3 versus 4±3 minutes, P=0.19), and total duration of teleconsultations (44±19 versus 45±21 minutes, P=0.98). Technical quality of mobile teleconsultations was rated worse on both sides, but this did not affect the ability to make remote clinical decisions like initiating thrombolysis (17% versus 13% of all, P=0.32). Conclusions— Teleconsultation using a laptop workstation and broadband mobile telecommunication was technically stable and allowed remote clinical decision-making. There remain disadvantages regarding videoconference quality on the hub side and lack of video transmission to the spoke side.

Prehospital stroke diagnostics based on neurological examination and transcranial ultrasound

BackgroundTranscranial color-coded sonography (TCCS) has proved to be a fast and reliable tool for the detection of middle cerebral artery (MCA) occlusions in a hospital setting. In this feasibility study on prehospital sonography, our aim was to investigate the accuracy of TCCS for neurovascular emergency diagnostics when performed in a prehospital setting using mobile ultrasound equipment as part of a neurological examination.MethodsFollowing a ‘911 stroke code’ call, stroke neurologists experienced in TCCS rendezvoused with the paramedic team. In patients with suspected stroke, TCCS examination including ultrasound contrast agents was performed. Results were compared with neurovascular imaging (CTA, MRA) and the final discharge diagnosis from standard patient-centered stroke care.ResultsWe enrolled ‘232 stroke code’ patients with follow-up data available in 102 patients with complete TCCS examination. A diagnosis of ischemic stroke was made in 73 cases; 29 patients were identified as ‘stroke mimics’. MCA occlusion was diagnosed in ten patients, while internal carotid artery (ICA) occlusion/high-grade stenosis leading to reversal of anterior cerebral artery flow was diagnosed in four patients. The initial working diagnosis ‘any stroke’ showed a sensitivity of 94% and a specificity of 48%. ‘Major MCA or ICA stroke’ diagnosed by mobile ultrasound showed an overall sensitivity of 78% and specificity of 98%.ConclusionsThe study demonstrates the feasibility and high diagnostic accuracy of emergency transcranial ultrasound assessment combined with neurological examinations for major ischemic stroke. Future combination with telemedical support, point-of-care analysis of blood serum markers, and probability algorithms of prehospital stroke diagnosis including ultrasound may help to speed up stroke treatment.

Stroke Thrombolysis in a Centralized and a Decentralized System (Helsinki and Telemedical Project for Integrative Stroke Care Network)

Background and Purpose— Intravenous thrombolysis with tissue-type plasminogen activator (tPA) for acute ischemic stroke is more effective when delivered early. Timely delivery is challenging particularly in rural areas with long distances. We compared delays and treatment rates of a large, decentralized telemedicine-based system and a well-organized, large, centralized single-hospital system. Methods— We analyzed the centralized system of the Helsinki University Central Hospital (Helsinki and Province of Uusimaa, Finland, 1.56 million inhabitants, 9096 km2) and the decentralized TeleStroke Unit network in a predominantly rural area (Telemedical Project for Integrative Stroke Care [TEMPiS], South-East Bavaria, Germany, 1.94 million inhabitants, 14 992 km2). All consecutive tPA treatments were prospectively registered. We compared tPA rates per total ischemic stroke admissions in the Helsinki and TEMPiS catchment areas. For delay comparisons, we excluded patients with basilar artery occlusions, in-hospital strokes, and those being treated after 270 minutes. Results— From January 1, 2011, to December 31, 2013, 912 patients received tPA in Helsinki University Central Hospital and 1779 in TEMPiS hospitals. Area-based tPA rates were equal (13.0% of 7017 ischemic strokes in the Helsinki University Central Hospital area versus 13.3% of 14 637 ischemic strokes in the TEMPiS area; P=0.078). Median prehospital delays were longer (88; interquartile range, 60–135 versus 65; 48–101 minutes; P<0.001) but in-hospital delays were shorter (18; interquartile range, 13–30 versus 39; 26–56 minutes; P<0.001) in Helsinki University Central Hospital compared with TEMPiS with no difference in overall delays (117; interquartile range, 81–168 versus 115; 87–155 minutes; P=0.45). Conclusions— A decentralized telestroke thrombolysis service can achieve similar treatment rates and time delays for a rural population as a centralized system can achieve for an urban population.

Hyperperfusion syndrome after MCA embolectomy – a rare complication?

Patient: Female, 78 Final Diagnosis: Cerebral hyperperfusion syndrome Symptoms: — Medication: — Clinical Procedure: Endovascular embolectomy Specialty: Neurology Objective: Unknown ethiology Background: Cerebral hyperperfusion syndrome (cHS) is a well known but rare complication after carotid endarterectomy, carotid angioplasty with stenting, and stenting of intracranial arterial stenosis. The clinical presentation may vary from acute onset of focal oedema (stroke-like presentation) and intracerbral hemorrhage to delayed (>24h hours after the procedure) presentation with seizures, focal motor weakness, or late intracerebral hemorrhage. The incidence of cHS after carotid endarterectomy ranges from 0–3% and defined as an increase of the ipsilateral cerebral blood flow up to 40% over baseline in ultrasound. Case Report: We present a case of a 78-year-old woman with an acute ischemic stroke due to left side middle cerebral artery territory with right sided hemiparesis and aphasia (NIHSS 16). After systemic thrombolysis embolectomy using a retractable stent (Solitaire® device) was performed and resulted in complete and successful recanalization of MCA including its branches about 210 minutes after symptom onset but, partial dislocation of thrombotic material into the anterior cerebral artery (ACA). Conclusions: Cerebral hyperperfusion syndrome should be considered in patients with clinical deterioration after successful recanalisation and the early diagnosis and treatment may be important for neurological outcome after endovascular embolectomy

Intracranial hemorrhage: frequency, location, and risk factors identified in a TeleStroke network.

Intracranial hemorrhages are associated with high rates of disability and mortality. Telemedicine in general provides clinical healthcare at a distance by using videotelephony and teleradiology and is used particularly in acute stroke care medicine (TeleStroke). TeleStroke considerably improves quality of stroke care (for instance, by increasing thrombolysis) and may be valuable for the management of intracranial hemorrhages in rural hospitals and hospitals lacking neurosurgical departments, given that surgical/interventional therapy is only recommended for a subgroup of patients. The aim of this study was to analyze the frequency, anatomical locations of intracranial hemorrhage, risk factors, and the proportion of patients transferred to specialized hospitals. We evaluated teleconsultations conducted between 2008 and 2010 in a large cohort of patients consecutively enrolled in the Telemedical Project for Integrated Stroke Care (TEMPiS) network. In cases in which intracranial hemorrhage was detected, all images were re-examined and analyzed with a focus on frequency, location, risk factors, and further management. Overall, 6187 patients presented with stroke-like symptoms. Intracranial hemorrhages were identified in 631 patients (10.2%). Of these, intracerebral hemorrhages were found in 423 cases (67.0%), including 174 (41.1%) in atypical locations and 227 (53.7%) in typical sites among other locations. After 14 days of hospitalization in community facilities, the mortality rate in patients with intracranial hemorrhages was 15.1% (95/631). Two hundred and twenty-three patients (35.3%) were transferred to neurological/neurosurgical hospitals for diagnostic workup or additional treatment. Community hospitals are confronted with patients with intracranial hemorrhage, whose management requires specific neurosurgical and hematological expertise with respect to hemorrhage subtype and clinical presentation. TeleStroke networks help select patients who need advanced neurological and/or neurosurgical care. The relatively low proportion of interhospital transfers shown in this study reflects a differentiated decision process on the basis of both guidelines and standard operating procedures.

Octreotide LAR and Prednisone as Neoadjuvant Treatment in Patients with Primary or Locally Recurrent Unresectable Thymic Tumors: A Phase II Study

Therapeutic options to cure advanced, recurrent, and unresectable thymomas are limited. The most important factor for long-term survival of thymoma patients is complete resection (R0) of the tumor. We therefore evaluated the response to and the induction of resectability of primarily or locally recurrent unresectable thymomas and thymic carcinomas by octreotide Long-Acting Release (LAR) plus prednisone therapy in patients with positive octreotide scans. In this open label, single-arm phase II study, 17 patients with thymomas considered unresectable or locally recurrent thymoma (n = 15) and thymic carcinoma (n = 2) at Masaoka stage III were enrolled. Octreotide LAR (30 mg once every 2 weeks) was administered in combination with prednisone (0.6 mg/kg per day) for a maximum of 24 weeks (study design according to Fleming´s one sample multiple testing procedure for phase II clinical trials). Tumor size was evaluated by volumetric CT measurements, and a decrease in tumor volume of at least 20% at week 12 compared to baseline was considered as a response. We found that octreotide LAR plus prednisone elicited response in 15 of 17 patients (88%). Median reduction of tumor volume after 12 weeks of treatment was 51% (range 20%–86%). Subsequently, complete surgical resection was achieved in five (29%) and four patients (23%) after 12 and 24 weeks, respectively. Octreotide LAR plus prednisone treatment was discontinued in two patients before week 12 due to unsatisfactory therapeutic effects or adverse events. The most frequent adverse events were gastrointestinal (71%), infectious (65%), and hematological (41%) complications. In conclusion, octreotide LAR plus prednisone is efficacious in patients with primary or recurrent unresectable thymoma with respect to tumor regression. Octreotide LAR plus prednisone was well tolerated and adverse events were in line with the known safety profile of both agents.