Economic Evaluation of a Mobile Stroke Unit Service in Germany.

BACKGROUND: Lower global disability and higher quality of life among ischemic stroke patients was found to be associated with the dispatch of mobile stroke units (MSUs) among patients eligible for recanalizing treatments in the Berlin_Prehospital Or Usual Delivery of stroke care (B_PROUD) study. The current study assessed the cost-utility and cost-effectiveness of additional MSU dispatch using data from this prospective, controlled, intervention study. METHODS: Outcomes considered in the economic evaluation included quality-adjusted life years (QALYs) derived from the 3-level version of EQ-5D (EQ-5D-3L) and modified Rankin Scale (mRS) scores for functional outcomes 3-months after stroke. Costs were prospectively collected during the study by the MSU provider (Berlin Fire Brigade) and the B_PROUD research team. We focus our results on the societal perspective. As we aimed to determine the economic consequences of the intervention beyond the study's follow-up period, both care costs and QALYs were extrapolated over 5 years. RESULTS: The additional MSU dispatch resulted in an incremental €40,984 per QALY. The best-case scenario and the worst-case scenario yielded additional costs of, respectively, €24,470.76 and €61,690.88 per QALY. In the cost-effectiveness analysis, MSU dispatch resulted in incremental costs of €81,491 per survival without disability. The best-case scenario and the worst-case scenario yielded additional costs of, respectively, €44,455.30 and €116,491.15 per survival without disability. INTERPRETATION: Among patients eligible for recanalizing treatments in ischemic stroke, MSU dispatch was associated with both higher QALYs and higher costs and is cost-effective when considering internationally accepted thresholds ranging from an additional €40,000 to €80,000 per QALY. ANN NEUROL 2023;93:942-951.

Effect of Mobile Stroke Unit Dispatch in all Patients with Acute Stroke or TIA.

OBJECTIVE: To determine the effect of additional mobile stroke unit (MSU) dispatch on functional outcomes among the full spectrum of stroke patients, regardless of subtype or potential contraindications to reperfusion therapies. METHODS: We used data from the nonrandomized Berlin-based B_PROUD study (02/2017 to 05/2019), in which MSUs were dispatched based solely on availability, and the linked B-SPATIAL stroke registry. All patients with final stroke or transient ischemic attack (TIA) diagnoses were eligible. The intervention under study was the additional dispatch of an MSU, an emergency physician-staffed ambulance equipped to provide prehospital imaging and thrombolytic treatment, compared to conventional ambulance alone. The primary outcome was the 3-month modified Rankin Scale (mRS) score, and the co-primary outcome was a 3-tiered disability scale. We identified confounders using directed acyclic graphs and obtained adjusted effect estimates using inverse probability of treatment weighting. RESULTS: MSUs were dispatched to 1,125 patients (mean age: 74 years, 46.5% female), while for 1,141 patients only conventional ambulances were dispatched (75 years, 49.9% female). After confounding adjustment, MSU dispatch was associated with more favorable 3-month mRS scores (common odds ratio [cOR] = 0.82; 95% confidence interval [CI]: 0.71-0.94). No statistically significant association was found with the co-primary outcome (cOR = 0.86; 9% CI: 0.72-1.01) or 7-day mortality (OR = 0.94; 95% CI: 0.59-1.48). INTERPRETATION: When considering the entire population of stroke/TIA patients, MSU dispatch improved 3-month functional outcomes without evidence of compromised safety. Our results are relevant for decision-makers since stroke subtype and treatment eligibility are unknown at time of dispatch. ANN NEUROL 2023;93:50-63.

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

Importance: Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. Objective: To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants: This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only). Exposure: Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). Main Outcomes and Measures: The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. Results: Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). Conclusions and Relevance: In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.

Low 25-hydroxyvitamin D, but not the bioavailable fraction of 25-hydroxyvitamin D, is a risk factor for multiple sclerosis.

BACKGROUND AND PURPOSE: Low 25-hydroxyvitamin D [25(OH)D] levels correlate with higher disease activity in patients with multiple sclerosis (MS). However, it is not clear whether low 25(OH)D levels directly contribute to increased disease activity or merely represent a consequence of reduced endogenous vitamin D synthesis in more disabled MS patients. Furthermore, recent data suggest that bioavailable vitamin D, which also integrates the levels of vitamin D binding proteins and albumin, could be a biologically more relevant parameter than 25(OH)D. METHODS: Measured de-seasonalized 25(OH)D3 and vitamin D binding protein and calculated bioavailable and free vitamin D were compared in the baseline serum samples of 76 patients with clinically isolated syndrome enrolled in a longitudinal observational study and in 76 age- and sex-matched healthy controls (HC). RESULTS: 25(OH)D3 levels were lower in patients with clinically isolated syndrome (P = 0.002) than in HC, and more patients (8/76, 10.5%) than HC (1/76, 1.3%) had 25(OH)D3 levels <25 nmol/l (P = 0.03). In contrast, levels of 25(OH)D2, vitamin D binding protein and calculated levels of free and bioavailable vitamin D did not differ between the two groups. CONCLUSIONS: Lower 25(OH)D3 levels already in the earliest phase of disease and in clinically hardly affected patients suggest that low 25(OH)D3 levels are rather a risk factor for than a consequence of MS. Nevertheless, because bioavailable vitamin D levels did not differ between the two groups, the mechanism underlying the association of 25(OH)D3 and MS does not appear to be related to reduced bioavailability of vitamin D.

Improved prehospital triage of patients with stroke in a specialized stroke ambulance: results of the pre-hospital acute neurological therapy and optimization of medical care in stroke study.

BACKGROUND AND PURPOSE: Specialized management of patients with stroke is not available in all hospitals. We evaluated whether prehospital management in the Stroke Emergency Mobile (STEMO) improves the triage of patients with stroke. METHODS: STEMO is an ambulance staffed with a specialized stroke team and equipped with a computed tomographic scanner and point-of-care laboratory. We compared the prehospital triage of patients with suspected stroke at dispatcher level who either received STEMO care or conventional care. We assessed transport destination in patients with different diagnoses. Status at hospital discharge was used as short-term outcome. RESULTS: From May 2011 to January 2013, 1804 of 6182 (29%) patients received STEMO care and 4378 of 6182 (71%) patients conventional care. Two hundred forty-five of 2110 (11.6%) patients with cerebrovascular events were sent to hospitals without Stroke Unit in conventional care when compared with 48 of 866 (5.5%; P<0.01%) patients in STEMO care. In patients with ischemic stroke, STEMO care reduced transport to hospitals without Stroke Unit from 10.1% (151 of 1497) to 3.9% (24 of 610; P<0.01). The delivery rate of patients with intracranial hemorrhage to hospitals without neurosurgery department was 43.0% (65 of 151) in conventional care and 11.3% (7 of 62) in STEMO care (P<0.01). There was a slight trend toward higher rates of patients discharged home in neurological patients when cared by STEMO (63.5% versus 60.8%; P=0.096). CONCLUSIONS: The triage of patients with cerebrovascular events to specialized hospitals can be improved by STEMO ambulances. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382862.

Effects of Mobile Stroke Unit dispatch on blood pressure management and outcomes in patients with intracerebral haematoma: Results from the Berlin_Prehospital Or Usual Care Delivery in acute Stroke (B_PROUD) controlled intervention study.

INTRODUCTION: In patients with acute intracerebral haemorrhage (ICH) and elevated systolic blood pressure (BP), guidelines suggest that systolic BP reduction to <140 mmHg should be rapidly initiated. Compared with conventional care, Mobile Stroke Units (MSUs) allow for earlier ICH diagnosis through prehospital imaging and earlier BP lowering. PATIENTS AND METHODS: ICH patients were prospectively evaluated as a cohort of the controlled B_PROUD-study in which MSU availability alone determined MSU dispatch in addition to conventional ambulance. We used inverse probability of treatment weighting to adjust for confounding to estimate the effect of additional MSU dispatch in ICH patients. Outcomes of interest were 7-day mortality (primary), systolic BP (sBP) at hospital arrival, dispatch-to-imaging time, largest haematoma volume, anticoagulation reversal, length of in-hospital stay, 3-month functional outcome. RESULTS: Between February 2017 and May 2019, MSUs were dispatched to 95 (mean age: 72 ± 13 years, 45% female) and only conventional ambulances to 78 ICH patients (mean age: 71 ± 12 years, 44% female). After adjusting for confounding, we found shorter dispatch-to-imaging time (mean difference: -17.75 min, 95% CI: -27.16 to -8.21 min) and lower sBP at hospital arrival (mean difference = -16.31 mmHg, 95% CI: -30.64 to -6.19 mmHg) in the MSU group. We found no statistically significant difference for the other outcomes, including 7-day mortality (adjusted odds ratio: 1.43, 95% CI: 0.68 to 3.31) or favourable outcome (adjusted odds ratio = 0.67, 95% CI: 0.27 to 1.67). CONCLUSIONS: Although MSU dispatch led to sBP reduction and lower dispatch-to-imaging time compared to conventional ambulance care, we found no evidence of better outcomes in the MSU dispatch group.

Prospective collection of blood plasma samples to identify potential biomarkers for the prehospital stroke diagnosis (ProGrEss-Bio): study protocol for a multicenter prospective observational study.

Introduction: Intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are well-established, evidence-based, time-critical therapies that reduce morbidity and mortality in acute ischemic stroke (AIS) patients. The exclusion of intracerebral hemorrhage (ICH) is mandatory and has been performed by cerebral imaging to date. Mobile stroke units (MSUs) have been shown to improve functional outcomes by bringing cerebral imaging and IVT directly to the patient, but they have limited coverage. Blood biomarkers clearly distinguishing between AIS, ICH, and stroke mimics (SM) could provide an alternative to cerebral imaging if concentration changes are detectable in the hyperacute phase after stroke with high diagnostic accuracy. In this study, we will take blood samples in a prehospital setting to evaluate potential biomarkers. The study was registered in the German Clinical Trials Register (https://drks.de/search/de) with the identifier DRKS00023063. Methods and analysis: We plan a prospective, observational study involving 300 patients with suspected stroke and symptom onset of ≤4.5 h before the collection of biomarkers. Study participants will be recruited from three sites in Berlin, Germany during MSU deployments. The focus of the study is the collection of blood samples from participants at the prehospital scene and from participants with AIS or ICH at a second-time point. All samples will be analyzed using targeted and untargeted analytical approaches. Study-related information about participants, including medical information and discharge diagnoses from the subsequent treating hospital, will be collected and documented in an electronic case report form (eCRF). Discussion: This study will evaluate whether a single blood biomarker or a combination of biomarkers can distinguish patients with AIS and ICH from patients with stroke and SM in the early phase after symptom onset in the prehospital setting. In addition, the kinetics of blood biomarkers in AIS and ICH patients will be investigated. Our goal is to evaluate new ways to reliably diagnose stroke in the prehospital setting and thus accelerate the application of evidence-based therapies to stroke patients.

Follow-up of Patients With Stroke Based on Opt-out Choice: Potential Approach for Acute Care Quality Registries or Observational Studies.

BACKGROUND AND OBJECTIVES: Restricting follow-up assessment of both interventional and observational studies to patients who provide informed consent introduces relevant selection bias-particularly by underrepresenting patients with neurologic communication deficits and impaired capacity to consent. Many patients who are initially unable to give consent may be willing to do so after recovery. Informing patients on study purposes and procedures with offering them the option of nonparticipation but not requesting explicit consent is called "opt-out" approach. We investigated whether an opt-out strategy yields meaningful follow-up rates in an acute stroke registry with an embedded controlled study. METHODS: The citywide Berlin-SPecific Acute Treatment in Ischemic or hAemorrhagic Stroke With Long Term Follow-up (B-SPATIAL) registry was designed to provide reliable information on process indicators and outcomes of specific acute stroke treatments to inform health care providers about quality of care and best practice strategies including the effects of a mobile stroke unit implementation. Because this information was regarded of high public interest, Berlin data protection authorities permitted data sampling without prior informed consent, using instead follow-up assessment on an "opt-out" basis. Patients were included if they had neurologic symptoms at ambulance or hospital arrival within 6 hours of onset and had a final diagnosis of stroke or TIA. Information on data collection and outcome assessment was sent by letter to patients 1 month before follow-up. RESULTS: From February 1, 2017, to January 31, 2020, a total of 10,597 patients were assessed. Thirty-one (0.3%) patients declined any data use, whereas 578 (5.5%) opted out of follow-up assessment. Of those not opting out (n = 9,988), functional outcome (modified Rankin Scale) was collected in 8,330 patients (83.4%) and vital status in 9,741 patients (97.5%). We received no complaints regarding data collection procedures. DISCUSSION: Opt-out-based follow-up collection offers a way to achieve high follow-up rates along with respecting patients' preferences.

Functional stroke outcomes after mobile stroke unit deployment - the revised protocol for the Berlin Prehospital Or Usual Delivery of acute stroke care (B_PROUD) part 2 study.

BACKGROUND: Studies investigating the Mobile Stroke Unit (MSU) concept have shown increased thrombolysis rates, reduced alarm-to-treatment times and improved prehospital triage. Yet, so far, there is no definite scientific proof of better functional outcome after MSU deployment compared to regular ambulances. METHODS: We provide a revised protocol for the second part of the B_PROUD trial as organization of the MSU dispatch did not meet the anticipated standards in the first part. B_PROUD is a pragmatic, prospective study comparing functional outcomes of treatment candidates with or without MSU care. Treatment candidates are defined as patients with a final diagnosis of ischemic stroke or transient ischemic attack, onset-to-dispatch-times ≤4 h, disabling symptoms not resolved at time of ambulance arrival, and the ability to ambulate prior to the qualifying event. These patients are included if their emergency call prompted a stroke alarm at the dispatch center during MSU operation hours (7 am-11 pm, Monday-Sunday) and if the emergency is located within the MSU operation area in Berlin, Germany. The intervention group consists of patients who are cared for by the MSU. When the MSU is already in operation for another emergency, MSU dispatches are handled by regular ambulances (about 45%). These dispatches create the control group. Blinded stroke physicians assess the modified Rankin Scale (mRS) score in recorded structured interviews 3 months after stroke. The primary outcome is the degree of disability and death over the full range of the mRS. As a change to the previously published protocol and only pertinent in case of more than 9% lost-to-follow-up, a co-primary outcome was introduced consisting of the proportions of death, new institutional care or severe disability in patients with additional use of information from registration offices. PERSPECTIVE: The results will inform parties involved in acute stroke care organization on the effectiveness of the MSU concept. TRIAL REGISTRATION: The protocol is registered in (NCT03931616) and has been approved by the ethical review committee of the Charité - University Medicine Berlin (EA4/109/15) on September 2, 2015. The study protocol of B_PROUD part 1 had been published in the International Journal of Stroke as "Berlin Prehospital Or Usual Delivery of acute stroke care (B_PROUD) - study protocol" (doi: 10.1177/1747493017700152) on March 22, 2017 [1] previous to first patient's registration.

Epstein-Barr virus antibodies in serum and DNA load in saliva are not associated with radiological or clinical disease activity in patients with early multiple sclerosis.

OBJECTIVE: To investigate the association of Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) immunoglobulin (Ig)G antibodies in serum as well as EBV DNA load in saliva with radiological and clinical disease activity in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS). METHODS: EBNA-1 and VCA immunoglobulin (Ig)G antibodies were determined in serum of 100 patients with CIS/early RRMS and 60 healthy controls. EBV DNA load was measured in saliva of 48 patients and 50 controls. Patients underwent clinical assessment with the Expanded Disability Status Scale (EDSS) and 3 Tesla magnetic resonance imaging at baseline and after a median of 20 months of follow-up (n = 63 for MRI, n = 71 for EDSS). The association of EBV parameters with occurrence of a second relapse, indicating conversion to clinically definite MS (CDMS), was evaluated over a median of 35 months of follow-up after the first clinical event (n = 89). RESULTS: EBNA-1 IgG antibody frequency (p = 0.00005) and EBNA-1 and VCA IgG antibody levels (p<0.0001 for both) were higher in patients than in controls. EBV DNA load in saliva did not differ between groups. Neither EBV antibody levels nor DNA load in saliva were associated with baseline or follow-up number or volume of T2-weighted (T2w) or contrast enhancing lesions, number of Barkhof criteria or the EDSS, or with the number of new T2w lesions, T2w lesion volume change or EDSS change on follow-up. Likewise, levels of EBV IgG antibodies in serum and DNA load in saliva were not associated with conversion to CDMS. CONCLUSIONS: While these findings confirm the association of EBV infection with early MS, neither EBNA-1 nor VCA IgG antibodies in serum nor EBV DNA load in saliva were associated with radiological or clinical disease activity in patients with CIS/early RRMS. These data are compatible with the concept that EBV may be a trigger for MS acting very early during the development of the disease.

Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study.

BACKGROUND: In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS). OBJECTIVE: To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection. METHODS: Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls. RESULTS: The median (range) number of γ-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL. CONCLUSION: γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.

Association of serum Epstein-Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis.

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection. A characteristic feature of MS is an intrathecal synthesis of immunoglobulin (Ig)G. In 90 patients with clinically isolated syndromes/early relapsing-remitting MS, serum antibodies to Epstein-Barr nuclear antigen-1, but not to EBV viral capsid antigen, rubella, or varicella zoster virus, were higher (p=0.03) in those with than those without a calculated intrathecal IgG synthesis >0% and correlated with the percentage (r=0.27, p=0.009) and concentration (r=0.27, p=0.012) of intrathecally produced IgG. These findings suggest a link between EBV infection and the events leading to intrathecal IgG synthesis in patients with MS.