Risk, Clinical Course, and Outcome of Ischemic Stroke in Patients Hospitalized With COVID-19: A Multicenter Cohort Study.

BACKGROUND AND PURPOSE: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. METHODS: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. RESULTS: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P=0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52-2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13-2.15]) than patients without stroke. CONCLUSIONS: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was ≈2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.

Sex-Related Differences in Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Several population-based studies found a higher case fatality after aneurysmal subarachnoid hemorrhage (ASAH) in women than in men. This may relate to differences in prognostic characteristics. We therefore assessed sex differences in prognosticators and outcome in ASAH patients. METHODS: From a prospectively collected ASAH database, we retrieved data on patients admitted from 1990 to 2010. We calculated prevalence ratios (PRs) with corresponding 95% confidence intervals (CIs) for prognosticators (clinical condition on admission, site and treatment of the aneurysm, and complications during the clinical course) and risk ratios (RRs) for in-hospital death and poor outcome (death or dependence) at 3 months. RRs were adjusted for possible confounding with Poisson regression analysis. RESULTS: Of the 1761 included patients, 1211 (68.8%) were women, who were 1.9 (95% CI: .5↔3.3) years older than men. PRs for women for the site of the aneurysm were 1.71 (95% CI: 1.38↔2.13) for the carotid artery, .68 (95% CI: .60↔.77) for the anterior communicating artery, 1.14 (95% CI: .92↔1.41) for the middle cerebral artery, and .85 (95% CI: .63↔1.13) for posterior circulation. PRs of other prognosticators were similar between sexes. The crude RR for in-hospital death for women was .91 (95% CI: .78↔1.05) and for poor outcome at 3 months was .95 (95% CI: .85↔1.06); both remained similar after adjustment. CONCLUSIONS: In this study, in-hospital death and poor outcome at 3 months did not differ between men and women. Women were slightly older than men and had different distributions of aneurysm sites, but not to an extent that it explained a sex difference in outcome.

Case fatality and functional outcome after spontaneous subarachnoid haemorrhage: A systematic review and meta-analysis of time trends and regional variations in population-based studies.

INTRODUCTION: A previous systematic review of population-based studies from 1973 to 2002 found a decrease in case fatality for spontaneous subarachnoid haemorrhage, but could not find a sufficient number of studies to assess changes in functional outcome. Since then, treatment has advanced distinctly. We assessed whether case fatality has decreased further and whether functional outcome has improved. PATIENTS AND METHODS: We searched PubMed and Web of Science for new population-based studies using the same criteria as in our previous systematic review. We assessed changes in case fatality and functional outcome over time using linear regression. RESULTS: We included 24 new studies with 827 patients and analysed 9542 patients described in 62 study periods between 1973 and 2017. Case fatality decreased by 0.3% (95% CI: -0.7 to 0.1) per year. In a sensitivity analysis excluding studies that did not provide 1-month outcome and outliers, the age and sex-adjusted decrease was 0.1% per year (95% CI: -0.9 to 0.6). The mean case fatality rate decreased from 47% (95% CI: 31-63) in the 1970s to 35% (95% CI: 30-39) in the 1990s, and remained stable in the 2000s (34%; 95% CI: 27-41) and 2010s (38%; 95% CI: 15-60). In 15 studies, the mean proportion of patients living independently increased by 0.2% per year (95%CI: -0.7 to 1.1) and the mean was 45% (95% CI: 39-50) in six studies that reported outcome after 12 months. DISCUSSION AND CONCLUSION: From 1973 to 2017, the case-fatality rate of spontaneous subarachnoid haemorrhage declined overall by 13.5%, but remained stable over the last two decades. The data on time trends in functional outcome were inconclusive.

Additional risk of hypertension and smoking for aneurysms in people with a family history of subarachnoid haemorrhage.

BACKGROUND: Smoking and hypertension increase the risk of aneurismal subarachnoid haemorrhage (SAH) two to threefold whereas a familial predisposition increases the risk sixfold. We assessed the additional risk of smoking and hypertension for the presence of an intracranial aneurysm (IA) in first-degree relatives of patients with familial SAH. METHODS: We studied first-degree relatives of patients with familial SAH who were screened for the presence of aneurysms. RRs with corresponding 95% CIs for the risk of IA were calculated for smoking and hypertension. RESULTS: The RRs were 1.5 (95% CI 0.7 to 3.2) for smoking, 1.9 (95% CI 1.0 to 3.7) for hypertension and 2.7 (95% CI 1.4 to 5.3) for smoking plus hypertension. The increased RR for hypertension was found in both women and men, but the increased RR for smoking was found in women only. CONCLUSION: The extent of the increased risk of smoking and hypertension for the presence of IA in first-degree relatives of patients with familial SAH is similar to that in patients without familial predisposition. Risk factor profiles should be included in future genetic studies.

Excess mortality and cardiovascular events in patients surviving subarachnoid hemorrhage: a nationwide study in Sweden.

BACKGROUND AND PURPOSE: Survivors of aneurysmal subarachnoid hemorrhage (SAH) may have an increased risk of cardiovascular events because of shared risk factors. We compared incidences of vascular diseases, vascular death, and all-cause death after SAH with those in the general population. METHODS: From the Swedish Hospital Discharge and Cause of Death registries, we identified patients with SAH between January 1987 and January 2003. Conditional on survival of 3 months after SAH, we calculated standardized mortality and incidence ratios with corresponding 95% CIs for vascular death, all-cause death, and fatal or nonfatal vascular diseases. Cumulative risks were estimated with survival analysis. RESULTS: Of 17,705 patients with SAH (mean age, 59.7 years; 59.5% women), 11,374 survived at least 3 months after SAH. During follow-up (mean, 6.8 years), 2152 (18.9%) died. The risk of death was 12.9% within 5 years, 23.6% within 10 years, and 35.4% within 15 years after SAH. The overall standardized mortality ratio was 1.57 (95% CI, 1.44 to 1.70) for vascular death and 1.61 (95% CI, 1.52 to 1.70) for all-cause death. The standardized mortality ratios were particularly high in younger individuals, ranging from 2.1 to 3.7 for vascular death and from 2.1 to 2.6 for all-cause death for patients between 50 and 65 years of age. The standardized incidence ratio for fatal or nonfatal vascular diseases was 1.51 (95% CI, 1.45 to 1.56). CONCLUSIONS: Mortality and risk of vascular diseases are increased in survivors of SAH. Prevention of new vascular diseases after SAH by management of risk factors seems important.

Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis.

BACKGROUND: In a systematic review, published in 1997, we found that the case fatality of aneurysmal subarachnoid haemorrhage (SAH) decreased during the period 1960-95. Because diagnostic and treatment strategies have improved and new studies from previously non-studied regions have been published since 1995, we did an updated meta-analysis to assess changes in case fatality and morbidity and differences according to age, sex, and region. METHODS: A new search of PubMed with predefined inclusion criteria for case finding and diagnosis identified reports on prospective population-based studies published between January, 1995, and July, 2007. The studies included in the previous systematic review were reassessed with the new inclusion criteria. Changes in case fatality over time and the effect of age and sex were quantified with weighted linear regression. Regional differences were analysed with linear regression analysis, and the regions of interest were subsequently defined as reference regions and compared with the other regions. FINDINGS: 33 studies (23 of which were published in 1995 or later) were included that described 39 study periods. These studies reported on 8739 patients, of whom 7659 [88%] were reported on after 1995. 11 of the studies that were included in the previous review did not meet the current, more stringent, inclusion criteria. The mean age of patients had increased in the period 1973 to 2002 from 52 to 62 years. Case fatality varied from 8.3% to 66.7% between studies and decreased 0.8% per year (95% CI 0.2 to 1.3). The decrease was unchanged after adjustment for sex, but the decrease per year was 0.4% (-0.5 to 1.2) after adjustment for age. Case fatality was 11.8% (3.8 to 19.9) lower in Japan than it was in Europe, the USA, Australia, and New Zealand. The unadjusted decrease in case fatality excluding the data for Japan was 0.6% per year (0.0 to 1.1), a 17% decrease over the three decades. Six studies reported data on case morbidity, but these were insufficient to assess changes over time. INTERPRETATION: Despite an increase in the mean age of patients with SAH, case-fatality rates have decreased by 17% between 1973 and 2002 and show potentially important regional differences. This decrease coincides with the introduction of improved management strategies. FUNDING: Netherlands Organisation for Scientific Research; ZonMw.

Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases.

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6-110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6-72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.

Timing of aneurysm surgery in subarachnoid hemorrhage: a systematic review of the literature.

OBJECTIVE: Many practitioners favor early operation after aneurysmal rupture, but sound data supporting this practice are lacking. A systematic review was conducted to compare early aneurysm surgery (Days 0-3), intermediate surgery (Days 4-7), and late surgery (more than 7 d after subarachnoid hemorrhage). METHODS: We performed a MEDLINE search of the literature published between January 1974 and December 1998 and an additional manual search of selected journal titles from January 1998 to December 1998. Main outcome measures were death and poor outcome (defined as death or dependency) at the end of the follow-up period. Risk ratios (RRs) and corresponding 95% confidence intervals (CIs) were calculated; patients planned for late surgery were used as the reference. RESULTS: Identified were 1 randomized clinical trial and 268 observational studies, of which only 10 studies (assessing a total of 1814 patients) fulfilled a set of minimum requirements for methodological quality. In the trial, the RR of poor outcome was 0.42 (95% CI, 0.17-1.04) for patients planned for early surgery and 1.07 (95% CI, 0.56-2.05) for intermediate surgery. In analyses with data from the 11 included studies, the RR of poor outcome for patients in good clinical condition at admission was 0.41 (95% CI, 0.34-0.51) for early surgery and 0.47 (95% CI, 0.32-0.69) for intermediate surgery. For patients in poor clinical condition at admission, the RR of poor outcome was 0.84 (95% CI, 0.67-1.05) for early surgery and 0.54 (95% CI, 0.24-1.22) for intermediate surgery. Adjustment of the RRs for year of publication, study design, and aneurysm location yielded essentially the same results, as did a sensitivity analysis after exclusion of the data from the randomized trial. CONCLUSION: This meta-analysis suggests that both early and intermediate surgical treatment improve outcome after aneurysmal subarachnoid hemorrhage--in particular for patients in good clinical condition at admission. However, this impression is derived only from an indirect comparison between different cohorts of patients. Sound evidence on the best timing of surgery is still lacking. Observational studies with better methods--and ideally a new randomized trial--are needed.

Long-term outcome after aneurysmal subarachnoid hemorrhage-risks of vascular events, death from cancer and all-cause death.

Smoking and hypertension are risk factors for aneurysmal subarachnoid hemorrhage (aSAH), but also for other cardiovascular diseases and cancer. Few prospective data are available on the very long term risks of vascular diseases and vascular, cancer-related and overall death after aSAH. We determined vascular events and survival status in 1,765 patients with aSAH admitted to our center from 1985 to 2010. Cumulative risks were estimated with survival analysis. We compared risks of vascular, cancer-related and all-cause death with the general population with standardized mortality ratios (SMRs). Incidences of vascular events and death were compared with those after TIA/minor stroke. Conditional on surviving 3 months after aSAH, the risk of death was 8.7 % (95 % CI 7.3-10.1) within 5 years, 17.9 % (16.1-19.9) within 10 years, 29.5 % (27.3-31.8) within 15 years, and 43.6 % (41.2-46.1) within 20 years after SAH. The SMR for all-cause death was 1.8 (1.6-2.1), for vascular death 2.0 (95 % CI 1.6-2.5) and for cancer-related death 1.2 (0.9-1.5; sensitivity analysis 1.4; 95 % CI 1.1-1.8). The increased SMR for all-cause death persevered up to 20 years after aSAH. Compared with TIA/minor stroke patients, the age- and sex-adjusted cumulative incidence on vascular events was lower for aSAH patients [hazard ratio (HR) 0.48; 95 % CI 0.40-0.57); the HR for all-cause death was 0.96 (95 % CI 0.84-1.10). After aSAH, risks of vascular events and death, and probably also that of cancer-related death, are higher than in the general population. Although the long-term risk of vascular events was lower in aSAH patients than in TIA/minor stroke patients, the risk of death was similar.

Risk of cardiovascular events and death in the life after aneurysmal subarachnoid haemorrhage: a nationwide study.

BACKGROUND AND AIM: The increased mortality rates of survivors of aneurysmal subarachnoid haemorrhage have been attributed to an increased risk of cardiovascular events in a registry study in Sweden. Swedish registries have however not been validated for subarachnoid haemorrhage and Scandinavian incidences of cardiovascular disease differ from that in Western European countries. We assessed risks of vascular disease and death in subarachnoid haemorrhage survivors in the Netherlands. METHODS: From the Dutch hospital discharge register, we identified all patients with subarachnoid haemorrhage admission between 1997 and 2008. We determined the accuracy of coding of the diagnosis subarachnoid haemorrhage for patients admitted to our centre. Conditional on survival of three-months after the subarachnoid haemorrhage, we calculated standardized incidence and mortality ratios for fatal or nonfatal vascular diseases, vascular death, and all-cause death. Cumulative risks were estimated with survival analysis. RESULTS: The diagnosis of nontraumatic subarachnoid haemorrhage was correct in 95·4% of 1472 patients. Of 11,263 admitted subarachnoid haemorrhage patients, 6999 survived more than three-months. During follow-up (mean 5·1 years), 874 (12·5%) died. The risks of death were 3·3% within one-year, 11·3% within five-years, and 21·5% within 10 years. The standardized mortality ratio was 3·4 (95% confidence interval: 3·1 to 3·7) for vascular death and 2·2 (95% confidence interval: 2·1 to 2·3) for all-cause death. The standardized incidence ratio for fatal or nonfatal vascular diseases was 2·7 (95% confidence interval: 2·6 to 2·8). CONCLUSIONS: Dutch hospital discharge and cause of death registries are a valid source of data for subarachnoid haemorrhage, and show that the increased mortality rate in subarachnoid haemorrhage survivors is explained by increased risks for vascular diseases and death.

Clinical and radiological heterogeneity in aneurysmal sub-arachnoid haemorrhage according to risk-factor profile.

BACKGROUND AND AIM: Risk factors for aneurysmal sub-arachnoid haemorrhage can be divided into environmental and inherited factors; the latter being presumed more important in young patients. We explored in young sub-arachnoid haemorrhage patients whether risk-factor profiles influence clinical and radiological characteristics of aneurysms and sub-arachnoid haemorrhage. METHODS: From the 2139 aneurysmal sub-arachnoid haemorrhage patients who had been entered in our prospectively collected database between January 1997 and August 2012, we retrieved data on young (18-40 years) aneurysmal sub-arachnoid haemorrhage patients and compared those with smoking or hypertension (atherogenic risk factors) with those without. Clinical and radiological characteristics were compared with risk ratios and corresponding 95% confidence intervals. Possible confounding by age and gender was adjusted with multivariable Poisson regression analysis. RESULTS: Patients with atherogenic risk factors (n = 113) were less often female (risk ratio: 0·7; 95% confidence interval: 0·6↔0·9), had less often a small aneurysm (risk ratio: 0·4; 95% confidence interval: 0·2↔0·7), and tended to have less often middle cerebral artery aneurysms (risk ratio: 0·5; 95% confidence interval: 0·3↔1·1) than the 29 patients without these risk factors. After adjustment for gender and age, patients with atherogenic risk factors had more often multiple aneurysms (risk ratio: 7·5; 95% confidence interval: 1·1↔52·9). There were no overt differences in the amount of cisternal and intraventricular blood, the shape of the aneurysm, and configuration of the circle of Willis between the patient groups. After adjustment for gender and age, patients with atherogenic risk factors had more often poor outcome (risk ratio: 3·8; 95% confidence interval: 1·0↔14·5). CONCLUSIONS: Young sub-arachnoid haemorrhage patients without atherogenic risk factors are rare. Clinical and radiological characteristics vary between sub-arachnoid haemorrhage patients with different risk-factor profiles. This clinical heterogeneity should be taken into account in future genetic and other etiological studies.

Age- and gender-specific time trend in risk of death of patients admitted with aneurysmal subarachnoid hemorrhage in the Netherlands.

BACKGROUND AND AIM: In a meta-analysis of population-based studies, case-fatality rates of subarachnoid hemorrhage have decreased worldwide by 17% between 1973 and 2002. However, age- and gender-specific decreases could not be determined. Because >10% of patients with subarachnoid hemorrhage die before reaching the hospital, this suggests that the prognosis for hospitalized subarachnoid hemorrhage patients has improved even more. We assessed age- and gender-specific time trends of the risk of death for hospitalized subarachnoid hemorrhage patients. METHODS: From the Dutch hospital discharge register (nationwide coverage), we identified 9403 patients admitted with subarachnoid hemorrhage in the Netherlands between 1997 and 2006. Changes in risk of death within this time frame and influence of age and gender were quantified with Poisson regression. RESULTS: The overall 30-day risk of death was 34.0% (95% confidence interval 33.1 ↔ 35.0%). After adjustment for age and gender, the annual decrease was 1.6% (95% confidence interval 0.5 ↔ 2.6%), which confers to a decrease of 13.4% (95% confidence interval 4.8 ↔ 21.2%) in the study period. The one-year risk of death decreased 2.0% per year (95% confidence interval 1.1 ↔ 2.9%). The decrease in risk of death was mainly found in the period 2003-2005, was not found for patients ≥ 65 years and was statistically significant for men, but not for women. CONCLUSIONS: The decrease in risk of death for patients admitted in the Netherlands with subarachnoid hemorrhage is overall considerable, but unevenly distributed over age and gender. Further research should focus on reasons for improved survival (improved diagnostics, improved treatment) and reasons why improvement has not occurred for women and for patients in older age categories.

Massive intraventricular haemorrhage from aneurysmal rupture: patient proportions and eligibility for intraventricular fibrinolysis.

Massive intraventricular haemorrhage (IVH) complicating aneurysmal subarachnoid haemorrhage (SAH) is associated with a poor prognosis. Small observational studies suggest favourable results from fibrinolysis of the intraventricular blood. We performed an observational study on IVH in a large series of patients with SAH to assess the proportion of patients that may benefit from fibrinolytic treatment. From our prospective database we retrieved patients with aneurysmal SAH admitted between January 2000 and January 2005. We calculated the proportion of patients with massive IVH and the proportion of patients that are eligible for fibrinolysis on basis of clinical and CT-scan characteristics and assessed neurological outcome in a treatment strategy without fibrinolysis. Poor neurological condition was defined as World Federation of Neurological Surgeons scale 4 and 5, poor outcome as death or dependence 3 months after SAH. Of the 573 patients admitted with aneurysmal SAH, 59 (10%; 95% confidence interval CI 8-13%) had massive IVH, of which 55 were in poor clinical condition. For these 55 patients, the case-fatality rate was 78% (95% CI 66-88%) and the proportion with poor outcome 91% (95% CI 81-97%). Of the 55 patients, 31 (56%, and 5% of all patients SAH within the study period) fulfilled our eligibility criteria and were considered suitable for intraventricular fibrinolysis. At 3 months, 30 of these 31 eligible patients (97%; 95% CI 85-100%) had a poor outcome. Massive IVH occurs in 10% of patients with aneurysmal SAH. Half of these patients may benefit from intraventricular fibrinolysis. Without fibrinolysis outcome is almost invariably poor in these patients.