[Position paper on stroke aftercare of the German Stroke Society-Part 1: long-term care after stroke: status quo of the reality and deficits of care in Germany]. / Positionspapier Schlaganfallnachsorge der Deutschen Schlaganfall-Gesellschaft ­ Teil 1: Nachsorge nach einem Schlaganfall: Status quo der Versorgungsrealität und Versorgungsdefizite in Deutschland.

The acute treatment of stroke patients in Germany is of a very high standard, guaranteed by its system of stroke units. Stroke as a disease has an acute phase followed by a chronic phase that requires a high level of qualified aftercare given by multidisciplinary and interdisciplinary teams. In 2020, the German Stroke Society (DSG) founded a commission for long-term stroke care. The aim is to evaluate the current situation of long-term aftercare and suggest improvements for its structure. In this paper the status quo of aftercare is presented and possible deficits are identified. Contributions of various stakeholders from the German healthcare system are analyzed and different projects for post-acute care are presented. Germany has no acknowledged structured aftercare concepts for patients after stroke. The general practitioner-based care is currently the focus of patient management but without a greater, more coordinated integration of neurologists, guideline-led and quality-controlled aftercare will be harder to implement in the future. The assignment of duties and the necessary training standards for the specialist groups in order to comply with the guidelines do not exist. Besides medical health, the needs of physical, social and emotional domains are too seldom considered by a multiprofessional care team. Further developments of a regional care management concept are discussed. The results and costs of any aftercare concepts must be evaluated before widespread implementation.

[Position paper on stroke aftercare of the German Stroke Society-Part 2: concept for a comprehensive stroke aftercare]. / Positionspapier Schlaganfallnachsorge der Deutschen Schlaganfall-Gesellschaft ­ Teil 2: Konzept für eine umfassende Schlaganfallnachsorge.

Long-term management after stroke has not been standardized in contrast to acute and rehabilitative stroke care. The fragmented outpatient sector of healthcare allows a high degree of flexibility but also variability in the quality of care provided. The commission on long-term stroke care of the German Stroke Society developed a concept on how to provide standardized multiprofessional long-term stroke care with a focus on patient-centered comprehensive care. We propose a diagnostic work-up in stages, with an initial patient-reported screening, followed by an adapted in-depth assessment of affected domains. This includes internistic domains (management of risk factors) and also genuine neurological domains (spasticity, cognitive deficits etc.) that must be considered. This information is then merged with patient expectations and prioritization to a standardized treatment plan. Special challenges for the implementation of such a comprehensive care system are the intersectoral and intrasectoral communication between healthcare providers, patients and relatives, the need to create a compensation system for providers and the establishment of appropriate quality management services. Digital health applications are helpful tools to provide aspects of diagnostics, treatment and communication in long-term stroke care.

[Position paper on stroke aftercare of the German Stroke Society-Part 3: structural concepts for future forms of care of stroke aftercare]. / Positionspapier Schlaganfallnachsorge der Deutschen Schlaganfall-Gesellschaft ­ Teil 3: Strukturelle Konzepte für zukünftige Versorgungsformen der Schlaganfallnachsorge.

BACKGROUND: Irrespective of the great impact stroke exerts on the society as a whole and far-reaching advances in acute treatment and rehabilitation of stroke, so far outpatient services for post-stroke care have not been established on a national level in Germany. OBJECTIVE AND METHODS: Against the background of this contemporary lack of care, in May 2020 the German Stroke Society (DSG) established the stroke aftercare commission. This position paper discusses structural models of future services addressing outpatient post-stroke care. RESULTS AND DISCUSSION: The specialized care by a neurologist should be central to a multidisciplinary, interprofessional and transsectoral treatment. Structural concepts of post-stroke care must take regional differences but also effective strategies for quality control into account. Certification processes and appropriate financing of follow-up registries at state and federal levels may pave the way for improvement over the medium term. Structured outpatient post-stroke care services should be open to all subgroups of stroke patients. Additionally, innovative technologies can make an important contribution to post-stroke care; however, the implementation of specialized services demands adequate funding as well as separate financial incentives for the providers. The solution must carefully balance the advantages and disadvantages of the specific care and financing models. Currently the discussion of new models of post-stroke care is gaining new momentum, which opens up perspectives for the advancement of the otherwise still insufficient contemporary care structures.

Cross-sectional study on patients' understanding and views of the informed consent procedure of a secondary stroke prevention trial.

BACKGROUND AND PURPOSE: Improving understanding of study contents and procedures might enhance recruitment into studies and retention during follow-up. However, data in stroke patients on understanding of the informed consent (IC) procedure are sparse. METHODS: We conducted a cross-sectional study among ischemic stroke patients taking part in the IC procedure of an ongoing cluster-randomized secondary prevention trial. All aspects of the IC procedure were assessed in an interview using a standardized 20-item questionnaire. Responses were collected within 72 h after the IC procedure and analyzed quantitatively and qualitatively. Participants were also asked their main reasons for participation. RESULTS: A total of 146 stroke patients (65 ± 12 years old, 38% female) were enrolled. On average, patients recalled 66.4% (95% confidence interval = 65.2%-67.5%) of the content of the IC procedure. Most patients understood that participation was voluntary (99.3%) and that they had the right to withdraw consent (97.1%); 79.1% of the patients recalled the study duration and 56.1% the goal. Only 40.3% could clearly state a benefit of participation, and 28.8% knew their group allocation. Younger age, higher graduation, and allocation to the intervention group were associated with better understanding. Of all patients, 53% exclusively stated a personal and 22% an altruistic reason for participation. CONCLUSIONS: Whereas understanding of patient rights was high, many patients were unable to recall other important aspects of study content and procedures. Increased attention to older and less educated patients may help to enhance understanding in this patient population. Actual recruitment and retention benefit of an improved IC procedure remains to be tested in a randomized trial.

Generalized anxiety is a predictor of impaired quality of life in patients with atrial fibrillation: Findings from the prospective observational ARENA study.

OBJECTIVE: Atrial fibrillation (AF) is associated with impaired health-related quality of life (HRQoL), an increased risk of morbidity, and mortality. Traditional AF-related outcomes (e.g., AF recurrence) primarily demonstrate the physiological benefits of AF management but do not focus on the benefits experienced subjectively by the patient (i.e., patient-reported outcomes), which have been suggested as optimal endpoints in AF intervention studies. The aim of this study is to identify medical and psychological factors associated with impaired HRQoL at 1-year follow-up. METHODS: Using data from the prospective observational multicenter ARENA study in patients with AF, we analyzed associations between medical factors, anxiety, and HRQoL at 1-year follow-up assessed using 5-level EuroQoL-5D. RESULTS: In 1353 AF patients (mean age 71.4 ± 10.3 years, 33.8% female), none of the medical predictors (e.g., heart disease) or history of cardioversion were associated with HRQoL at the 1-year follow-up. Higher generalized anxiety (ß = -0.114, p < .001) but not cardiac anxiety (ß = -0.006, p = .809) at baseline predicted decreased HRQoL, independent of confounding variables and patients' medical status. Furthermore, the worsening of patients' generalized anxiety was associated with decreased HRQoL (ß = -0.091, p < .001). In contrast, the improvement of generalized anxiety over time predicted higher HRQoL (ß = 0.097, p < .001). Finally, the worsening of patients' cardiac anxiety over time was associated with decreased HRQoL (ß = -0.081, p < .001). CONCLUSION: Our results highlight the importance of anxiety as a predictor of future HRQoL in patients with AF. Additional studies to examine the impact of anxiety treatment on HRQoL in this population are needed. CLINICAL TRIAL REGISTRATION: The investigators registered on ClinicalTrials.gov (NCT02978248) on November 30, 2016 https://clinicaltrials.gov/ct2/show/NCT02978248.

Morphometry of structural disconnectivity indicators in subjects at risk and in age-matched patients with schizophrenia.

Structural disconnectivity has been hypothesized as being accountable for the pathophysiology of schizophrenia. Morphometric variables suitable for the empirical study of disconnectivity were studied aiming at the research question whether empirical indicators for disconnectivity are already informative in subjects at risk (SAR) and in young matched patients diagnosed with schizophrenia (SZ). In MRI data of subjects of the two diagnostic groups SZ and SAR, the size of the corpus callosum (CC) as indicator for interhemispherical long distance connections and the gyrification index (GI) as indicator for cortico-cortical connections were analyzed compared to a healthy controls (HC). Each subgroup consists of 21 subjects matched for sex and age. Measurements of the CC and GI were estimated in manually performed tracing procedures. GI data revealed significant differences between the diagnostic groups of both SAR and SZ as compared to HC in the frontal and parietal cortices. Measurements of total CC yielded no significant differences between diagnostic groups. The results are suggestive for impaired cortico-cortical connections as indicated by gyrification changes in SZ and also in SAR, whereas interhemispherical connectivity at the same time appears to be unaffected.

The impact of regional deprivation on stroke incidence, treatment, and mortality in Germany.

BACKGROUND: Regional deprivation has been shown to be an influential factor in stroke incidence risk. However, there is a paucity of knowledge on regional differences in stroke incidence and mortality in Germany. METHODS: We assessed data from the Diagnosis Related Groups statistics (2016-2019) and the German Federal Registry of Physicians (2019). Negative binomial regression analysis was used to examine the association between the German Index of Multiple Deprivation 2015 covering 401 districts and district-free cities in Germany and stroke incidence, treatment, and mortality. RESULTS: The adjusted rate ratios of stroke incidence and mortality with the highest deprivation level compared with the least deprived area were 1.161 (95% CI [1.143, 1.179]) and 1.193 (95% CI [1.148, 1.239]), respectively. Moreover, this study revealed that physician density was higher in district-free cities compared to districts. CONCLUSIONS: Our results indicate that regional deprivation is associated with incident and mortality cases of stroke, necessitating a more targeted approach to stroke prevention in deprived regions.

The structured ambulatory post-stroke care program for outpatient aftercare in patients with ischaemic stroke in Germany (SANO): an open-label, cluster-randomised controlled trial.

BACKGROUND: Patients with ischaemic stroke are at risk of recurrent stroke. In this study, we aimed to compare the effect of a structured ambulatory post-stroke care programme versus usual care on recurrent vascular events and death and control of cardiovascular risk factors. METHODS: We did a prospective, open-label, cluster-randomised controlled trial (SANO) at stroke centres in regions of Germany. A cluster was defined as a region in which acute stroke care is provided by a participating stroke centre. Patients were eligible for participation if they were aged 18 years or older, had no severe disabilities before the index stroke (modified Rankin scale 0-1), had at least one modifiable cardiovascular risk factor, and presented within 14 days of symptom onset of their first ischaemic stroke. The participating regions were randomly assigned (1:1) to the intervention and control group (usual care) by the statistician using block randomisation (block sizes of six), stratified by rural and urban regions. In intervention regions, a cross-sectoral multidisciplinary network was established to provide a 1-year organisational and patient-centred intervention. Due to the type of intervention, masking of participants and study physicians was not possible. Endpoint adjudication was performed by an independent endpoint adjudication committee who were masked to cluster allocation. The primary endpoint was a composite of recurrent stroke, myocardial infarction, and all-cause death within 12 months after baseline assessment, assessed in the modified intention-to-treat (mITT) population, which included all patients who did not withdraw consent and completed the primary endpoint assessment at 12 months. This study was registered with the German Clinical Trials Register, DRKS00015322. FINDINGS: Between Jan 1, 2019 and Dec 22, 2020, 36 clusters were assessed for eligibility, of which 30 were randomly assigned to the intervention group (n=15 clusters) or control group (n=15 clusters). No clusters dropped out of the study. 1203 (86%) of 1396 enrolled patients in the intervention group and 1283 (92%) of 1395 enrolled patients in the control group were included in the mITT population. The primary endpoint was confirmed in 64 (5·3%) of 1203 patients in the intervention group and 80 (6·2%) of 1283 patients in the control group (unadjusted odds ratio [OR] 0·80 [95% CI 0·49-1·30]; adjusted OR [aOR] 0·95 [95% CI 0·54-1·67]). All-cause deaths occurred in 31 (2·4%) of 1203 patients in the intervention group and 12 (1·0%) of 1283 patients in the control group. The incidence of serious adverse events was higher in the intervention group (266 [23·1%] of 1151) than the control group (106 [9·2%] of 1152). Falls (134 [11·4%] of 1203 patients in the intervention group; 39 [3·3%] of 1152 patients in the control group), hypertensive crisis (55 [4·7%]; 34 [2·8%]), and diagnosis of depression (51 [4·3%]; 13 [1·1%]) were the most frequent adverse events in both groups. No differences were identified in the rate of readmission to hospital between groups. INTERPRETATION: No differences were identified between patients with ischaemic stroke in the intervention group and control group with regard to the incidence of vascular events 1 year after baseline assessment, despite positive effects with regard to the control of some cardiovascular risk factors. Longer-term effects and other potentially favourable effects on stroke-related sequelae and quality of life require further evaluation. FUNDING: Innovation Fund of the Federal Joint Committee.

Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology.

BACKGROUND AND PURPOSE: The importance of cancer-associated hypercoagulability as a possible stroke etiology in patients with cancer has received relatively little attention to date. A recent study has suggested that cancer-associated hypercoagulation may be of special importance in the absence of conventional stroke mechanisms. METHODS: We identified patients with ischemic stroke sequentially admitted to our stroke center with the additional diagnosis of active and malignant cancer from 2002 to 2011. By using our prospectively collected stroke, MRI, and laboratory data banks, the etiology and risk factors of stroke, types of cancer, deep vein thrombosis/pulmonary embolism, d-dimer levels, and diffusion-weighted imaging lesion patterns were compared to an age- and sex-matched control group. Patients with cancer with a conventional stroke etiology and patients with an unidentified and/or cancer-associated stroke etiology were analyzed separately. RESULTS: One hundred forty patients with cancer and 140 control subjects were included. Unidentified stroke (P<0.001) and infarction in multiple vascular territories (P<0.001) were significantly more frequent and d-dimer levels significantly higher (P<0.05) in patients with cancer. Vice versa, risk factors such as hypertension (P<0.05) and hyperlipidemia (P<0.01) were more prevalent in control subjects. Deep vein thrombosis and pulmonary embolism were more frequent (P<0.01) and d-dimer levels higher (P<0.01) in the patients with unidentified and/or cancer-associated stroke etiology compared to the patients with cancer with a conventional stroke etiology. Lung and pancreatic cancer were significantly overrepresented and d-dimer levels higher in these patients compared with other patients with cancer (P<0.01). CONCLUSIONS: Our data confirm the concept of cancer-associated hypercoagulation as a widely underestimated important stroke risk factor in patients with cancer, especially in those with severely elevated d-dimer levels and in the absence of conventional risk factors.

Symptom Severity and Health-Related Quality of Life in Patients with Atrial Fibrillation: Findings from the Observational ARENA Study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with impaired health-related quality of life (HRQoL), high symptom severity, and poor cardiovascular outcomes. Both clinical and psychological factors may contribute to symptom severity and HRQoL in AF. METHODS: Using data from the observational Atrial Fibrillation Rhine-Neckar Region (ARENA) trial, we identified medical and psychosocial factors associated with AF-related symptom severity using European Heart Rhythm Association symptom classification and HRQoL using 5-level EuroQoL- 5D. RESULTS: In 1218 AF patients (mean age 71.1 ± 10.5 years, 34.5% female), female sex (OR 3.7, p < 0.001), preexisting coronary artery disease (CAD) (OR 1.7, p = 0.020), a history of cardioversion (OR 1.4, p = 0.041), cardiac anxiety (OR 1.2; p < 0.001), stress from noise (OR 1.4, p = 0.005), work-related stress (OR 1.3, p = 0.026), and sleep disturbance (OR 1.2, p = 0.016) were associated with higher AF-related symptom severity. CAD (ß = -0.23, p = 0.001), diabetes mellitus (ß = -0.25, p < 0.001), generalized anxiety (ß = -0.30, p < 0.001), cardiac anxiety (ß = -0.16, p < 0.001), financial stress (ß = -0.11, p < 0.001), and sleep disturbance (ß = 0.11, p < 0.001) were associated with impaired HRQoL. CONCLUSIONS: Psychological characteristics, preexisting CAD, and diabetes may play an important role in the identification of individuals at highest risk for impaired HRQoL and high symptom severity in patients with AF.

Trial design and pilot phase results of a cluster-randomised intervention trial to improve stroke care after hospital discharge - The structured ambulatory post-stroke care program (SANO).

INTRODUCTION: Previous studies showed insufficient control of cardiovascular risk factors (CVRF) and high stroke recurrence rates among ischemic stroke patients in Germany. Currently, no structured secondary prevention program exists in clinical routine. We present the trial design and pilot phase results of a complex intervention to improve stroke care after hospital discharge in Germany. PATIENTS AND METHODS: SANO is a cluster-randomized trial with 30 participating regions across Germany aiming to enrol 2,790 patients (drks.de, DRKS00015322). Study intervention combines both structural and patient-centred elements. Study development was based on the Medical Research Council framework for complex interventions. In 15 intervention regions, a cross-sectoral multidisciplinary network is established to enhance CVRF control as well as detection and treatment of post-stroke complications. Recommendations on CVRF are based on high-quality secondary prevention guidelines. Study physicians use motivational interviewing and agree with patients on therapeutic targets. While hospitalised, patients also receive dietary counselling and a health-passport to track their progress. During regular visits, CVRF management and potential complications are monitored. The intervention is compared to 15 regions providing usual care. The primary endpoint is the combination of recurrent stroke, myocardial infarction and death assessed 12 months after enrolment and adjudicated in a blinded manner. RESULTS: Eighteen patients were enrolled in a pilot phase that demonstrated feasibility of patient recruitment and study procedures. CONCLUSION: SANO is investigating a program to reduce outcome events after ischemic stroke by implementing a complex intervention. If successful, the program may be implemented in routine care on national level in Germany.

Immediate Neutrophil-Variable-T Cell Receptor Host Response in Bacterial Meningitis.

Bacterial meningitis is a life-threatening disease that evokes an intense neutrophil-dominated host response to microbes invading the subarachnoid space. Recent evidence indicates the existence of combinatorial V(D)J immune receptors in neutrophils that are based on the T cell receptor (TCR). Here, we investigated expression of the novel neutrophil TCRαß-based V(D)J receptors in cerebrospinal fluid (CSF) from human patients with acute-phase bacterial meningitis using immunocytochemical, genetic immunoprofiling, cell biological, and mass spectrometric techniques. We find that the human neutrophil combinatorial V(D)J receptors are rapidly induced in CSF neutrophils during the first hours of bacterial meningitis. Immune receptor repertoire diversity is consistently increased in CSF neutrophils relative to circulating neutrophils and phagocytosis of baits directed to the variable immunoreceptor is enhanced in CSF neutrophils during acute-phase meningitis. Our results reveal that a flexible immune response involving neutrophil V(D)J receptors which enhance phagocytosis is immediately initiated at the site of acute bacterial infection.

Off-label use of IV t-PA in patients with intracranial neoplasm and cavernoma.

BACKGROUND: The safety of systemic thrombolysis in patients with intracranial tumor and cavernoma are unknown. So far evidence is limited to a number of case reports and few case series or unspecified data based on population-based analysis. Our aim was to comprehend the risk of systemic thrombolysis in these patients. METHODS: Patients with additional evidence of intracranial tumor or cavernoma who received IV tissue plasminogen activator (t-PA) treatment at our comprehensive stroke center over a period of 7 years were identified in our stroke database and compared to the same number of matched control subjects without any evidence of intracranial tumor and cavernoma. Clinical history and imaging patterns before and after t-PA therapy were individually reviewed for each patient. RESULTS: Thirty-four patients with additional evidence of meningioma (19/34), cavernoma (13/34) or malignant intracranial neoplasm (2/34) were identified. The incidence of secondary intracranial hemorrhage observed showed no difference between control subjects (9/34, 26%) and patients (6/34, 18%; p = 0.56). Symptomatic hemorrhage in patients with meningioma or cavernoma could not be observed. Likewise, the prevalence of stroke mimics showed no difference between patients (8/34, 24%) and control subjects (5/34, 15%; p = 0.54). However, both patients with malignant intracranial neoplasm presented with a stroke mimic and intracranial hemorrhage was observed in one of them. CONCLUSIONS: In compliance with existing evidence, treatment in patients with meningioma and cavernoma appears to be safe and reasonable, while the therapy should be avoided in patients with malignant intracranial neoplasm with blood-brain barrier disruption.

Chorea in a patient with cryopyrin-associated periodic syndrome.

OBJECTIVE: To describe a patient with cryopyrin-associated periodic syndrome (CAPS) with an uncommon neurologic phenotype and a rare underlying genetic mutation. RESULTS: Our patient had CAPS with a rare NLPR3 missense mutation (p.Tyr859Cys) in exon 6 with chorea as the major symptom. Clinical symptoms were associated with persistent inflammatory changes of the CSF and serum and included elevated anticardiolipin immunoglobulin G; MRI showed prolonged gadolinium enhancement of 2 chronic inflammatory lesions. Conventional immunosuppressive treatment with prednisolone and hydroxychloroquine was insufficient. Neurologic symptoms, laboratory/chemical measures, and MRI abnormalities almost completely normalized following interleukin (IL)-1ß blockade with anakinra. CONCLUSIONS: This case is unique for its uncommon neurologic phenotype, the rare underlying genetic mutation, and the long course of the disease as well as almost complete recovery following appropriate therapy. In addition, the chronic inflammatory white matter lesions observed on brain MRI and the responsiveness to IL-1ß blockade with anakinra are unusual.

DWI Lesion Patterns in Cancer-Related Stroke--Specifying the Phenotype.

BACKGROUND: Due to the lack of specific diagnostic markers, the diagnosis of cancer-related stroke strongly depends on its phenotype. Distinct DWI lesion patterns with involvement of multiple vascular territories have been reported repeatedly in cancer-related stroke but have not been addressed in detail in a selected cohort of prospectively recruited cancer patients with emphasis on hypercoagulable conditions. PATIENTS AND METHODS: Ischemic stroke patients with known malignant cancer activity, laboratory evidence of strong plasmatic hypercoagulation (D-dimer levels > 3 µg/ml) and without competing stroke etiologies according to the recently introduced ASCOD (A - atherosclerosis, S - small vessel disease, C - cardiac pathology, O - other cause, and D - dissection) classification of evidence-rated etiology of stroke subtypes were included in the analysis. Cerebral MRI on admission was reviewed with respect to ischemic lesion patterns. RESULTS: Thirty-two patients met the inclusion criteria. The mean D-dimer levels were 15.39 µg/ml (± 10.84). Acute infarction in ≥ 2 vascular territories was present in 27/32 (84%) patients. (Micro-) embolic scattering of infarction was present in 25/32 (78%) patients. Evidence for previous, potentially oligosymptomatic infarction was found in 16 (50%) patients, demonstrated by the additional presence of subacute or chronic ischemic lesions. CONCLUSION: When excluding competing embolic and nonembolic stroke etiologies, the pattern of scattered DWI lesions in multiple vascular supply territories strongly dominates the phenotype of cancer-related stroke. Additionally, evidence of recurrent infarction is frequent in this cohort of patients. This is not only important for the diagnosis of cancer-related stroke itself but may prove helpful for the identification of cancer-related stroke patients with unknown malignancy at the time of stroke manifestation and evaluation of strategies for secondary prevention.