How a thrombectomy service can reduce hospital deficit: a cost-effectiveness study.

BACKGROUND: There is level 1 evidence for cerebral thrombectomy with thrombolysis in acute large vessel occlusion. Many hospitals are now contemplating setting up this life-saving service. For the hospital, however, the first treatment is associated with an initial high cost to cover the procedure. Whilst the health economic benefit of treating stroke is documented, this is the only study to date performing matched-pair, patient-level costing to determine treatment cost within the first hospital episode and up to 90 days post-event. METHODS: We conducted a retrospective coarsened exact matched-pair analysis of 50 acute stroke patients eligible for thrombectomy. RESULTS: Thrombectomy resulted in significantly more good outcomes (mRS 0-2) compared to matched controls (56% vs 8%, p = 0.001). More patients in the thrombectomy group could be discharged home (60% vs 28%), fewer were discharged to nursing homes (4% vs 16%), residential homes (0% vs 12%) or rehabilitation centres (8% vs 20%). Thrombectomy patients had fewer serious adverse events (n = 30 vs 86) and were, on average, discharged 36 days earlier. They required significantly fewer physiotherapy sessions (18.72 vs 46.49, p = 0.0009) resulting in a median reduction in total rehabilitation cost of £4982 (p = 0.0002) per patient. The total cost of additional investigations was £227 lower (p = 0.0369). Overall, the median cost without thrombectomy was £39,664 per case vs £22,444, resulting in median savings of £17,221 (p = 0.0489). CONCLUSIONS: Mechanical thrombectomy improved patient outcome, reduced length of hospitalisation and, even without procedural reimbursement, significantly reduced cost to the thrombectomy providing hospital.

Sphingosine prevents binding of SARS-CoV-2 spike to its cellular receptor ACE2.

Sphingosine has been shown to prevent and eliminate bacterial infections of the respiratory tract, but it is unknown whether sphingosine can be also employed to prevent viral infections. To test this hypothesis, we analyzed whether sphingosine regulates the infection of cultured and freshly isolated ex vivo human epithelial cells with pseudoviral particles expressing SARS-CoV-2 spike (pp-VSV-SARS-CoV-2 spike) that served as a bona fide system mimicking SARS-CoV-2 infection. We demonstrate that exogenously applied sphingosine suspended in 0.9% NaCl prevents cellular infection with pp-SARS-CoV-2 spike. Pretreatment of cultured Vero epithelial cells or freshly isolated human nasal epithelial cells with low concentrations of sphingosine prevented adhesion of and infection with pp-VSV-SARS-CoV-2 spike. Mechanistically, we demonstrate that sphingosine binds to ACE2, the cellular receptor of SARS-CoV-2, and prevents the interaction of the receptor-binding domain of the viral spike protein with ACE2. These data indicate that sphingosine prevents at least some viral infections by interfering with the interaction of the virus with its receptor. Our data also suggest that further preclinical and finally clinical examination of sphingosine is warranted for potential use as a prophylactic or early treatment for coronavirus disease-19.

Impact of mobile stroke units.

Since its first introduction in clinical practice in 2008, the concept of mobile stroke unit enabling prehospital stroke treatment has rapidly expanded worldwide. This review summarises current knowledge in this young field of stroke research, discussing topics such as benefits in reduction of delay before treatment, vascular imaging-based triage of patients with large-vessel occlusion in the field, differential blood pressure management or prehospital antagonisation of anticoagulants. However, before mobile stroke units can become routine, several questions remain to be answered. Current research, therefore, focuses on safety, long-term medical benefit, best setting and cost-efficiency as crucial determinants for the sustainability of this novel strategy of acute stroke management.

Effects of a Feedback-Demanding Stroke Clock on Acute Stroke Management: A Randomized Study.

BACKGROUND AND PURPOSE: This randomized study aimed to evaluate whether the use of a stroke clock demanding active feedback from the stroke physician accelerates acute stroke management. METHODS: For this randomized controlled study, a large-display alarm clock was installed in the computed tomography room, where admission, diagnostic work-up, and intravenous thrombolysis occurred. Alarms were set at the following target times after admission: (1) 15 minutes (neurological examination completed); (2) 25 minutes (computed tomography scanning and international normalized ratio determination by point-of-care laboratory completed); and (3) 30 minutes (intravenous thrombolysis started). The responsible stroke physician had to actively provide feedback by pressing a buzzer button. The alarm could be avoided by pressing the button before time out. Times to therapy decision (primary end point, defined as the end of all diagnostic work-up required for decision for or against recanalizing treatment), neurological examination, imaging, point-of-care laboratory, needle, and groin puncture were assessed by a neutral observer. Functional outcome (modified Rankin Scale) was assessed at day 90. RESULTS: Of 107 participants, 51 stroke clock patients exhibited better stroke-management metrics than 56 control patients. Times from door to (1) end of all indicated diagnostic work-up (treatment decision time; 16.73 versus 26.00 minutes, P<0.001), (2) end of neurological examination (7.28 versus 10.00 minutes, P<0.001), (3) end of computed tomography (11.17 versus 14.00 minutes, P=0.002), (4) end of computed tomography angiography (14.00 versus 17.17 minutes, P=0.001), (5) end of point-of-care laboratory testing (12.14 versus 20.00 minutes, P<0.001), and (6) needle times (18.83 versus 47.00 minutes, P=0.016) were improved. In contrast, door-to-groin puncture times and functional outcomes at day 90 were not significantly different. CONCLUSIONS: This study showed that the use of a stroke clock demanding active feedback significantly improves acute stroke-management metrics and, thus, represents a potential low-cost strategy for streamlining time-sensitive stroke treatment.

Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma.

To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.

Aeromedical Retrieval for Stroke in Australia.

INTRODUCTION: Rural, remote, and Indigenous stroke patients have worse stroke outcomes than urban Australians. This may be due to lack of timely access to expert facilities. OBJECTIVES: We aimed to describe the characteristics of patients who underwent aeromedical retrieval for stroke, estimate transfer times, and investigate if flight paths corresponded with the locations of stroke units (SUs) throughout Australia. METHODS: Prospective review of routinely collected Royal Flying Doctor Service (RFDS) data. Patients who underwent an RFDS aeromedical retrieval for stroke, July 2014-June 2018 (ICD-10 codes: I60-I69), were included. To define the locations of SUs throughout Australia, we accessed data from the 2017 National Stroke Audit. The main outcome measures included determining the characteristics of patients with an in-flight diagnosis of stroke, their subsequent pickup and transfer locations, and corresponding SU and imaging capacity. RESULTS: The RFDS conducted 1,773 stroke aeromedical retrievals, consisting of 1,028 (58%) male and 1,481 (83.5%) non-Indigenous and 292 (16.5%) Indigenous patients. Indigenous patients were a decade younger, 56.0 (interquartile range [IQR] 45.0-64.0), than non-Indigenous patients, 66.0 (IQR 54.0-76.0). The most common diagnosis was "stroke not specified," reflecting retrieval locations without imaging capability. The estimated median time for aeromedical retrieval was 238 min (95% confidence interval: 231-244). Patients were more likely to be transferred to an area with SU and imaging capability (both p < 0.0001). CONCLUSION: Stroke patients living in rural areas were younger than those living in major cities (75 years, Stroke Audit Data), with aeromedically retrieved Indigenous patients being a decade younger than non-Indigenous patients. The current transfer times are largely outside the time windows for reperfusion methods. Future research should aim to facilitate more timely diagnosis and treatment of stroke.

Mobile Stroke Unit in the UK Healthcare System: Avoidance of Unnecessary Accident and Emergency Admissions.

BACKGROUND: Acute stroke patients are usually transported to the nearest hospital regardless of their required level of care. This can lead to increased pressure on emergency departments and treatment delay. OBJECTIVE: The aim of the study was to explore the benefit of a mobile stroke unit (MSU) in the UK National Health Service (NHS) for reduction of hospital admissions. METHODS: Prospective cohort audit observation with dispatch of the MSU in the East of England Ambulance Service area in Southend-on-Sea was conducted. Emergency patients categorized as code stroke and headache were included from June 5, 2018, to December 18, 2018. Rate of avoided admission to the accident and emergency (A&E) department, rate of admission directly to target ward, and stroke management metrics were assessed. RESULTS: In 116 MSU-treated patients, the following diagnoses were made: acute stroke, n = 33 (28.4%); transient ischaemic attacks, n = 13 (11.2%); stroke mimics, n = 32 (27.6%); and other conditions, n = 38 (32.8%). Pre-hospital thrombolysis was administered to 8 of 28 (28.6%) ischaemic stroke patients. Pre-hospital diagnosis avoided hospital admission for 29 (25.0%) patients. As hospital treatment was indicated, 35 (30.2%) patients were directly triaged to the stroke unit, 1 patient (0.9%) even directly to the catheter laboratory. Thus, only 50 (43.1%) patients required transfer to the A&E department. Moreover, the MSU enabled thrombolysis with a median dispatch-to-needle time of 42 min (interquartile range, 40-60). CONCLUSION: This first deployment of an MSU in the UK NHS demonstrated improved triage decision-making for or against hospital admission and admission to the appropriate target ward, thereby reducing pressure on strained A&E departments.

Early poststroke seizures following thrombolysis and/or thrombectomy for acute stroke: Clinical and stroke characteristics.

In this retrospective study, we explored the clinical and stroke characteristics of patients treated with thrombolysis and/or mechanical thrombectomy for an acute stroke and experiencing early poststroke seizures within 7 days of the cerebrovascular accident. Patients with prior epilepsy, primary intracerebral hemorrhage or transient ischemic attacks, or taking antiepileptic drugs were excluded. We retrospectively identified 32 patients admitted between 2010 and 2016 (mean age 75 years; range: 49-90; 14 females and 18 males). A cortical stroke was found in more than 70% of patients. Most epileptic seizures were focal aware (46.7%) or generalized convulsive (43.3%). The median time between stroke onset and seizure occurrence was 2 days; in 75.9% of the cases, seizures occurred within the first 3 days. This retrospective case series is the largest published so far providing details on clinical features of patients with early poststroke seizures following different reperfusion therapies, not only restricted to intravenous (i.v.) thrombolysis. Early poststroke seizures following reperfusion therapies are associated with cortical stroke involvement, are usually focal without impairment of awareness or generalized convulsive, and occur mostly within the first 3 days. Further studies are needed to clarify whether the low prevalence of focal impaired awareness seizures (and nonconvulsive seizures/status) is real or reflects the failure to recognize and correctly diagnose this seizure type in the acute poststroke period (risk of underascertainment due to the lack of systematic video-electroencephalogram (EEG) recording in patients with stroke and difficulties in recognizing these seizures). This article is part of the Special Issue "Seizures & Stroke".

Pharmacological Inhibition of Acid Sphingomyelinase Ameliorates Experimental Autoimmune Encephalomyelitis.

BACKGROUND/AIMS: Multiple sclerosis (MS) is one of the most common autoimmune disorders of the central nervous system (CNS) and the leading cause of neurological disability among young adults in the Western world. We have previously shown that the acid sphingomyelinase plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. METHODS: We induced adoptively transferred EAE in wildtype and acid sphingomyelinase-deficient mice. In addition, we immunized mice with MOGaa35-55 to induce active EAE and treated the mice with amitriptyline, a functional inhibitor of the acid sphingomyelinase. We investigated symptoms of EAE, blood-brain barrier integrity and neuroinflammation. RESULTS: In the model of adoptively transferred EAE we demonstrate that expression of acid sphingomyelinase in the recipients rather than on transferred encephalitogenic T cells contributes to the clinical development of EAE symptoms. To test if pharmacological targeting of acid sphingomyelinase can be explored for the development of novel therapies for MS, we inhibited acid sphingomyelinase with amitriptyline in mice in which EAE was induced by active immunization. We demonstrate that pharmacological inhibition of acid sphingomyelinase using amitriptyline protects against the development of EAE and markedly attenuates the characteristic detrimental neuroinflammatory response. CONCLUSION: The studies identify the acid sphingomyelinase as a novel therapeutic target for treating MS patients.

Collateral Automation for Triage in Stroke: Evaluating Automated Scoring of Collaterals in Acute Stroke on Computed Tomography Scans.

Computed tomography angiography (CTA) collateral scoring can identify patients most likely to benefit from mechanical thrombectomy and those more likely to have good outcomes and ranges from 0 (no collaterals) to 3 (complete collaterals). In this study, we used a machine learning approach to categorise the degree of collateral flow in 98 patients who were eligible for mechanical thrombectomy and generate an e-CTA collateral score (CTA-CS) for each patient (e-STROKE SUITE, Brainomix Ltd., Oxford, UK). Three experienced neuroradiologists (NRs) independently estimated the CTA-CS, first without and then with knowledge of the e-CTA output, before finally agreeing on a consensus score. Addition of the e-CTA improved the intraclass correlation coefficient (ICC) between NRs from 0.58 (0.46-0.67) to 0.77 (0.66-0.85, p = 0.003). Automated e-CTA, without NR input, agreed with the consensus score in 90% of scans with the remaining 10% within 1 point of the consensus (ICC 0.93, 0.90-0.95). Sensitivity and specificity for identifying favourable collateral flow (collateral score 2-3) were 0.99 (0.93-1.00) and 0.94 (0.70-1.00), respectively. e-CTA correlated with the Alberta Stroke Programme Early CT Score (Spearman correlation 0.46, p < 0.001) highlighting the value of good collateral flow in maintaining tissue viability prior to reperfusion. In conclusion, -e-CTA provides a real-time and fully automated approach to collateral scoring with the potential to improve consistency of image interpretation and to independently quantify collateral scores even without expert rater input.

Mobile Stroke Units - Cost-Effective or Just an Expensive Hype?

PURPOSE OF REVIEW: Acute stroke is a treatable disease. Nevertheless, only a minority of patients obtain guideline-adjusted therapy. One major reason is the small time window in which therapies have to be administered in order to reverse or mitigate brain injury and prevent disability. The Mobile Stroke Unit (MSU) concept, available for a decade now, is spreading worldwide, comprising ambulances, fully equipped with computed tomography, laboratory unit and telemedicine connection to the stroke centre and staffed with a specialised stroke team. Besides its benefits, this concept adds a relevant amount of costs to health services. RECENT FINDINGS: The feasibility of the MSU and its impact on reducing treatment times have been proven by several research trials. In addition, pre-hospital stroke diagnosis including computed tomographic angiography analysis facilitates correct triage of patients, needing mechanical recanalization, thereby reducing the number of secondary or inter-hospital transfers. Even so, the concept is not yet fully implemented on a broad scale. One reason is the still open question of cost-effectiveness. There are assumptions based on the randomised trials of MSUs hinting towards an acceptable amount of money per quality-adjusted life years and overall cost-effectiveness. Up to now, neither a prospective analysis nor a consideration of secondary transfer avoidance is available. The MSU concept is an innovative and impactful strategy to improve stroke management, especially in times of constraints in healthcare economics and health care professionals. Prospective information is needed to answer the cost-effectiveness question satisfactorily.

Acute Occlusions of Dual-Layer Carotid Stents After Endovascular Emergency Treatment of Tandem Lesions.

BACKGROUND AND PURPOSE: A new generation of carotid artery stents that uses a second micromesh layer to reduce embolic events during carotid artery stenting has recently been introduced. The purpose of this study was to compare acute occlusion rates of these new dual-layer stents with those of single-layer stents in the setting of emergency carotid artery stenting with intracranial mechanical thrombectomy in acute ischemic stroke. METHODS: Consecutive patients with acute tandem (intra- and extracranial) lesions of the anterior circulation who were endovascularly treated at our institution were identified from our registry of neuroendovascular interventions. Clinical, angiographic, and neuroimaging data were analyzed. End points included acute occlusions of the carotid stents (within 72 hours after stenting) and symptomatic intracerebral hemorrhage. RESULTS: Forty-seven patients were included. Dual-layer stents (n=20) had a significantly higher rate of acute occlusions than single-layer stents (n=27; 45% versus 3.7%; P=0.001; odds ratio, 21.3; 95% confidence interval, 2.4-188.4). There were no significant differences in the rates of patients who had any antiplatelet or dual antiplatelet medication before admission, in the rates of postinterventional symptomatic intracerebral hemorrhage, the mean National Institutes of Health Stroke Scale scores at admission, or the modified Rankin Scale scores at discharge. CONCLUSIONS: The recently introduced dual-layer stents have a higher risk of acute occlusion compared with single-layer stents in the treatment of acute stroke.

Regulation of Arthritis Severity by the Acid Sphingomyelinase.

BACKGROUND/AIMS: Rheumatoid arthritis is a chronic autoimmune disease hallmarked by inflammation in synovial joints. Treatment is hampered by the lack of a cure and current disease-modifying drugs are associated with potentially severe toxicities. METHODS: We investigated arthritis severity by measuring joint swelling and pro-inflammatory cytokine production in a murine experimental model of inflammatory arthritis (antigen-induced arthritis). We analyzed acid sphingomyelinase knock-out mice and wild-type littermates, as well as mice treated with the pharmacological acid sphingomyelinase inhibitor amitriptyline. RESULTS: Genetic ablation or pharmacological inhibition of acid sphingomyelinase reduced joint swelling and levels of pro-inflammatory cytokines in the arthritic joint. CONCLUSION: We identified acid sphingomyelinase as a novel druggable target in rheumatoid arthritis. Functional inhibitors of acid sphingomyelinase have been clinically used for decades, are well tolerated and suitable for long-term treatment. They would be immediately available for clinical development as a novel rheumatoid arthritis therapy.

Blockade of Experimental Multiple Sclerosis by Inhibition of the Acid Sphingomyelinase/Ceramide System.

BACKGROUND: Multiple sclerosis (MS) is a severe and common autoimmune disorder of the central nervous system. Despite the availability of several novel treatment options, the disease is still poorly controlled, since the pathophysiological mechanisms are not fully understood. METHODS: We tested the role of the acid sphingomyelinase/ceramide system in a model of MS, i.e. experimental autoimmune encephalomyelitis (EAE). Mice were immunized with myelin-oligodendrocyte glycoprotein and the development of the disease was analyzed by histology, immunological tests and clinical assessment in wildtype and acid sphingomyelinase (Asm)-deficient mice. RESULTS: Genetic deficiency of acid sphingomyelinase (Asm) protected against clinical symptoms in EAE and markedly attenuated the characteristic detrimental neuroinflammatory response. T lymphocyte adhesion, integrity of tight junctions, blood-brain barrier disruption and subsequent intracerebral infiltration of inflammatory cells were blocked in Asm-deficient mice after immunization. This resulted in an almost complete block of the development of disease symptoms in these mice, while wildtype mice showed severe neurological symptoms typical for EAE. CONCLUSION: Activation of the Asm/ceramide system is a central step for the development of EAE. Our findings may serve to identify novel therapeutic strategies for MS patients.

Prehospital Computed Tomography Angiography in Acute Stroke Management.

BACKGROUND: An ambulance equipped with a computed tomography (CT) scanner, a point-of-care laboratory, and telemedicine capabilities (mobile stroke unit [MSU]) has been shown to enable the delivery of thrombolysis to stroke patients directly at the emergency site, thereby significantly decreasing time to treatment. However, work-up in an MSU that includes CT angiography (CTA) may also potentially facilitate triage of patients directly to the appropriate target hospital and specialized treatment, according to their individual vascular pathology. METHODS: Our institution manages a program investigating the prehospital management of patients with suspicion of acute stroke. Here, we report a range of scenarios in which prehospital CTA could be relevant in triaging patients to the appropriate target hospital and to the individually required treatment. RESULTS: Prehospital CTA by use of an MSU allowed to detect large vessel occlusion of the middle cerebral artery in one patient with ischemic stroke and occlusion of the basilar artery in another, thereby allowing rational triage to comprehensive stroke centers for immediate intra-arterial treatment. In complementary cases, prehospital imaging not only allowed diagnosis of parenchymal hemorrhage with a spot sign indicating ongoing bleeding in one patient and of subarachnoid hemorrhage in another but also clarified the underlying vascular pathology, which was relevant for subsequent triage decisions. CONCLUSION: Defining the vascular pathology by CTA directly at the emergency site may be beneficial in triaging patients with various cerebrovascular diseases to the most appropriate target hospital and specialized treatment.

First Automated Stroke Imaging Evaluation via Electronic Alberta Stroke Program Early CT Score in a Mobile Stroke Unit.

BACKGROUND: Recently, a mobile stroke unit (MSU) was shown to facilitate acute stroke treatment directly at the emergency site. The neuroradiological expertise of the MSU is improved by its ability to detect early ischemic damage via automatic electronic (e) evaluation of CT scans using a novel software program that calculates the electronic Alberta Stroke Program Early CT Score (e-ASPECTS). METHODS: The feasibility of integrating e-ASPECTS into an ambulance was examined, and the clinical integration and utility of the software in 15 consecutive cases evaluated. RESULTS: Implementation of e-ASPECTS onto the MSU and into the prehospital stroke management was feasible. The values of e-ASPECTS matched with the results of conventional neuroradiologic analysis by the MSU team. The potential benefits of e-ASPECTS were illustrated by three cases. In case 1, excluding early infarct signs supported the decision to directly perform prehospital thrombolysis. In case 2, in which stroke was caused by large-vessel occlusion, the high e-ASPECTS value supported the decision to initiate intra-arterial treatment and triage the patient to a comprehensive stroke center. In case 3, the e-ASPECTS value was 10, indicating the absence of early infarct signs despite pre-existing cerebral microangiopathy and macroangiopathy, a finding indicating the program's robustness against artefacts. CONCLUSIONS: This study on the integration of e-ASPECTS into the prehospital stroke management via a MSU showed for the first time that such integration is feasible, and aids both decision regarding the treatment option and the triage regarding the most appropriate target hospital.

A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression.

Major depressive disorder is a severe and chronic illness with high lifetime prevalence and a high incidence of suicide as the cause of death for patients with this diagnosis. Major depressive disorder is often treated with anti-depressants. Although these drugs have been used for many years, their exact mode of action is still unknown. It has been suggested that many anti-depressants act by increasing the concentrations of serotonergic transmitters in the synaptic space. However, recent studies have examined the effects of anti-depressants on neurogenesis in the hippocampus, the restoration of hippocampal neuronal networks that may be affected by major depression, and the regulation of the hypothalamic-pituitary-adrenal axis by immature neurons in the hippocampus. Here, we present and discuss a novel hypothesis suggesting that these events are regulated by the concentrations of sphingolipids, in particular ceramide, in the hippocampus. These concepts suggest that the acid sphingomyelinase/ceramide system plays a central role in the pathogenesis of major depression and may be a novel target for anti-depressants.