Stroke Patients Without COVID-19 Symptoms: Is There a Need to Screen?

INTRODUCTION: COVID-19 patients who present with strokes but without typical COVID-19 symptoms have been described in small numbers. Despite the paucity of fever and respiratory symptoms, they remain capable of infecting others. The patient we discuss herein highlights the important issues of strokes as presenting events of COVID-19 infections, and how testing for COVID-19 in stroke patients, even when asymptomatic for COVID-19, can play an important role in infection control, clinical management and outcomes amidst this global pandemic. CASE REPORT: A 45-year-old male resident of a dormitory presented to our unit with acute vertigo and left-sided dysmetria. NIHSS was 2. The initial magnetic resonance imaging demonstrated infarction of the left cerebellar hemisphere, middle cerebellar peduncle and hemipons. An extensive work-up for stroke etiologies was unremarkable. Despite having no fever, respiratory symptoms, anosmia or ageusia, he was isolated and screened for COVID-19 due to his epidemiologic risks, with multiple residents from his dormitory being recently diagnosed with COVID-19. Confirming our suspicion, his respiratory samples returned positive for COVID-19. His D-dimer levels returned normal. Thereafter, the patient underwent posterior decompression surgery due to worsening edema caused by the cerebellar infarct. He was started on antiplatelet therapy and recovered significantly a month from presentation with an modified Rankin Sore of 2. He remained without typical COVID-19 symptoms. CONCLUSION: Our patient's case clearly supports the screening for COVID-19 in stroke patients who are without COVID-19 symptoms, appreciating the significant value it adds to infection control, clinical management, and outcomes amidst this global pandemic.

The Relationship Between Ambient Air Pollution and Acute Ischemic Stroke: A Time-Stratified Case-Crossover Study in a City-State With Seasonal Exposure to the Southeast Asian Haze Problem.

STUDY OBJECTIVE: Studies are divided on the short-term association of air pollution with stroke. Singapore is exposed to seasonal transboundary haze. We aim to investigate the association between air pollution and stroke incidence in Singapore. METHODS: We performed a time-stratified case-crossover analysis on all ischemic stroke cases reported to the Singapore Stroke Registry from 2010 to 2015. Exposure on days was compared with control days on which exposure did not occur. Control days were chosen on the same day of the week earlier and later in the same month in the same year. We fitted a conditional Poisson regression model to daily stroke incidence that included Pollutant Standards Index and environmental confounders. The index was categorized according to established classification (0 to 50=good, 51 to 100=moderate, and ≥101=unhealthy). We assessed the relationship between stroke incidence and Pollutant Standards Index in the entire cohort and in predetermined subgroups of individual-level characteristics. RESULTS: There were 29,384 ischemic stroke cases. Moderate and unhealthy Pollutant Standards Index levels showed association with stroke occurrence, with incidence risk ratio 1.10 (95% confidence interval 1.06 to 1.13) and 1.14 (95% confidence interval 1.03 to 1.25), respectively. Subgroup analyses showed generally significant association, except in Indians and nonhypertensive patients. The association was significant in subgroups aged 65 years or older, women, Chinese, nonsmokers and those with history of diabetes, hypertension, and hyperlipidemia. Stratified by age and smoking, the risk diminished in smokers of all ages. Risk remained elevated for 5 days after exposure. CONCLUSION: We found a short-term elevated risk of ischemic stroke after exposure to air pollution. These findings have public health implications for stroke prevention and emergency health services delivery.

Asian venous thromboembolism guidelines: updated recommendations for the prevention of venous thromboembolism.

The Asian venous thromboembolism (VTE) prophylaxis guidelines were first published in 2012. Since its first edition, the Asian Venous Thrombosis Forum (AVTF) working group have updated the Asian VTE epidemiology and reviewed issues that were not addressed in the previous guidelines. The authors noted that the rising incidence of VTE across Asia may be attributable to aging population, dietary changes, and increasing incidence of obesity and diabetes. The new additions in the guideline include role of thrombophilia in VTE, bleeding risk in Asians, individual risk assessment, updates in the prevention of VTE in medically ill, bariatric surgery, cancer, orthopedic and trauma patients. The influence of primary thrombophilia in perioperative VTE is still unclear. The secondary risk factors, however, are similar between Asians and Caucasians. The group found no evidence of increased risk of bleeding while using pharmacological agents, including the use of novel anti-coagulants. At present, Caprini risk assessment model is widely used for individual risk assessment. Further validation of this model is needed in Asia. In medically ill patients, pharmacological agents are preferred if there is no bleeding risk. Intermittent pneumatic compression device (IPC) is recommended in patients with bleeding risk but we do not recommend using graduated compressive stockings. In bariatric patients, data on VTE is lacking in Asia. We recommend following current international guidelines. A high index of suspicion should be maintained during postbariatric surgery to detect and promptly treat portomesenteric venous thrombosis. Different cancer types have different thrombotic risks and the types of surgery influence to a large extent the overall VTE risk. Cancer patients should receive further risk assessment. In patients with higher thrombotic risk, either due to predisposing risk or concomitant surgery, low molecular weight heparin is indicated. Different countries appear to have different incidence of VTE following trauma and major orthopedic surgery. We recommend mechanical prophylaxis using IPC as the main method and additional pharmacological prophylaxis if the thrombotic risk is high. As for obstetric practice, we propose adherence to the UK Greentop guideline that is widely accepted and utilized across Asia. To improve VTE thromboprophylaxis implementation in the region, we propose that there should be better health education, establishment of hospital-based guidelines and multidisciplinary collaboration.

Two decades of nation-wide community-based stroke support - The Singapore National Stroke Association.

The Singapore National Stroke Association, registered in 1996, offers support and information to stroke survivors and caregivers, and aims to raise public stroke awareness. In the last 20 years, we have developed programs to equip stroke survivors and caregivers with knowledge, life skills, comfort, and opportunities for socialization and reintegration. We have on-going public education and advocacy initiatives. Obtaining funding, member recruitment, volunteer retention, and leadership renewal are on-going challenges. Singapore National Stroke Association will continue to strive for the betterment of stroke survivors, their caregivers, and the public.

Inflammatory markers and their association with post stroke cognitive decline.

BACKGROUND: Population-based studies have demonstrated the association of inflammation and cognitive impairment. However, few studies to date have examined this association in ischemic stroke patients. AIMS: The study aims to determine the association between inflammatory markers and cognitive impairment. METHODS: Ischemic stroke patients with baseline neuropsychological assessments at three-months poststroke were followed up with annual neuropsychological assessments for up to five-years. Inflammatory markers (C-reactive protein, interleukin 1ß, interleukin 6, interleukin 8, interleukin 10, interleukin 12, and tumor necrosis factor-α) were assayed, and logistic regression analyses were performed to determine associations between inflammatory markers and both baseline cognitive status and subsequent cognitive decline. RESULTS: There were 243 ischemic stroke patients in the study. In multivariable ordinal logistic regression analysis, age, education, ethnicity, stroke subtype, and interleukin 8 (OR 1.23 CI 1.05-1.44) levels were independently associated with baseline cognitive status. In multivariable logistic regression analyses, age, gender, recurrent strokes, and interleukin 12 (OR 25.02 CI 3.73 to 168.03) were independent predictors of subsequent cognitive decline. CONCLUSIONS: Following ischemic stroke, higher serum interleukin 8 is independently associated with baseline cognitive impairment while higher serum interleukin 12 is associated with subsequent cognitive decline.

Retinal microvascular changes and risk of stroke: the Singapore Malay Eye Study.

BACKGROUND AND PURPOSE: To examine the relationship between retinal microvascular measures and incident stroke in an Asian Malay population. METHODS: We conducted a prospective, population-based cohort study of Asian Malay persons 40 to 80 years at baseline. Retinal microvascular signs were assessed from baseline retinal photographs including quantitative retinal microvascular parameters (caliber, branching angle, tortuosity, and fractal dimension) and qualitative retinopathy signs. Incident stroke cases were identified during the follow-up period. Cox proportional-hazards regression and incremental usefulness analysis (calibration, discrimination, and reclassification) were performed. RESULTS: A total of 3189 participants were free of prevalent stroke at baseline. During the follow-up (median, 4.41 years), 51 (1.93%) participants had an incident stroke event. In Cox proportional-hazards models adjusting for established stroke predictors (age, sex, systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, smoking, glycosylated hemoglobin, and antihypertensive medication), retinopathy (hazard ratio, 1.94; 95% confidence interval, 1.01-3.72) and larger retinal venular caliber (hazard ratio, 3.28; 95% confidence interval, 1.30-8.26, comparing fourth versus first quartiles) were associated with risk of stroke. Compared with the model with only established risk factors, the addition of retinal measures improved the prediction of stroke (C-Statistic 0.826 versus 0.792; P=0.017) and correctly reclassified 5.9% of participants with incident stroke and 3.4% of participants with no incident stroke. CONCLUSIONS: Retinal microvascular changes are related to an increased risk of stroke in Asian Malay, consistent with data from white populations. Retinal imaging improves the discrimination and stratification of stroke risk beyond that of established risk factors by a significant but small margin.

Microvascular structure and network in the retina of patients with ischemic stroke.

BACKGROUND AND PURPOSE: Microvascular disease has been implicated in the pathogenesis of stroke. The retina provides a window to assess microcirculation noninvasively. We studied the association between quantitatively measured retinal microvascular characteristics and acute ischemic stroke. METHODS: We conducted a case-control study with acute ischemic stroke patients recruited from a tertiary hospital in Singapore and controls from the Singapore Epidemiology of Eye Disease program matched by 10-year age strata, sex, and race. Strokes were classified using modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Retinal vascular parameters were measured from retinal fundus photographs using a computer program. Logistic regression models for stroke were constructed adjusting for age, sex, race, and additionally for smoking, hypertension, diabetes mellitus, and hypercholesterolemia. RESULTS: We included 557 ischemic stroke cases (261 lacunar, 185 large artery, and 54 cardioembolic stroke) and 557 controls. After adjusting for vascular risk factors, decreased arteriolar fractal dimension (odds ratio [OR] per standard deviation [SD] decrease, 2.28; 95% confidence interval [CI], 1.80-2.87) and venular fractal dimension (OR per SD decrease, 1.80; 95% CI, 1.46-2.23), increased arteriolar tortuosity (OR per SD increase, 1.56; 95% CI, 1.25-1.95), and venular tortuosity (OR per SD increase, 1.49; 95% CI, 1.27-1.76), narrower arteriolar caliber (OR per SD decrease, 2.79; 95% CI, 2.21-3.53), and wider venular caliber (OR per SD increase, 1.57; 95% CI, 1.27-1.95) were associated with stroke. Stratification by stroke subtypes and further adjustment for retinopathy signs revealed similar results. CONCLUSIONS: Patients with ischemic stroke have a sparser and more tortuous microvascular network in the retina. These findings provide insight into the structure and pattern of microcirculation changes in stroke.

Associations of ankle-brachial index (ABI) with cerebral arterial disease and vascular events following ischemic stroke.

OBJECTIVES: Low ankle-brachial index (ABI), indicative of peripheral arterial disease (PAD), is a risk factor for stroke. ABI has been shown to be associated with cerebral arterial disease and prognosis following stroke. We studied the associations of the degree of ABI lowering with extracranial carotid disease (ECD), intracranial large artery disease (ICLAD), and subsequent vascular events in a prospective cohort of acute ischemic stroke patients. METHODS: ABI, extracranial and intracranial cerebral arteries were assessed in a blinded manner. ABI was categorized into 0.9-1.3 (normal), 0.8-0.89 (mildly lowered) and <0.8 (severely lowered). Follow-up data at 1 year were obtained from standardized telephone interviews and verified with medical records. RESULTS: Among the 1311 patients, 73% had normal ABI, 13% had ABI 0.8-0.89 and 13% had ABI <0.8. Compared to patients with normal ABI, those with ABI<0.8 had higher prevalence of severe ECD (15% vs. 5%, p = 0.006) and ICLAD (72% vs. 48%, p = 0.003), even after adjustment for age, gender, hypertension, diabetes, hyperlipidemia, smoking, ischemic heart disease and atrial fibrillation (severe ECD p < 0.001, ICLAD p < 0.001). At 1 year, patients with ABI <0.8 had a higher incidence of composite vascular events (19% vs. 11%, p = 0.02), stroke (15% vs. 10%, p = 0.06) and myocardial infarction (4% vs. 2%, p = 0.07) than patients with normal ABI. CONCLUSION: Among ischemic stroke patients, large cerebral arterial disease and incidence of subsequent vascular events at 1 year were associated with severe ABI lowering <0.8, but not with mild ABI lowering (0.8-0.89).

RAPID automated patient selection for reperfusion therapy: a pooled analysis of the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) Study.

BACKGROUND AND PURPOSE: The aim of this study was to determine if automated MRI analysis software (RAPID) can be used to identify patients with stroke in whom reperfusion is associated with an increased chance of good outcome. METHODS: Baseline diffusion- and perfusion-weighted MRI scans from the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution study (DEFUSE; n=74) and the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET; n=100) were reprocessed with RAPID. Based on RAPID-generated diffusion-weighted imaging and perfusion-weighted imaging lesion volumes, patients were categorized according to 3 prespecified MRI profiles that were hypothesized to predict benefit (Target Mismatch), harm (Malignant), and no effect (No Mismatch) from reperfusion. Favorable clinical response was defined as a National Institutes of Health Stroke Scale score of 0 to 1 or a ≥ 8-point improvement on the National Institutes of Health Stroke Scale score at Day 90. RESULTS: In Target Mismatch patients, reperfusion was strongly associated with a favorable clinical response (OR, 5.6; 95% CI, 2.1 to 15.3) and attenuation of infarct growth (10 ± 23 mL with reperfusion versus 40 ± 44 mL without reperfusion; P<0.001). In Malignant profile patients, reperfusion was not associated with a favorable clinical response (OR, 0.74; 95% CI, 0.1 to 5.8) or attenuation of infarct growth (85 ± 74 mL with reperfusion versus 95 ± 79 mL without reperfusion; P=0.7). Reperfusion was also not associated with a favorable clinical response (OR, 1.05; 95% CI, 0.1 to 9.4) or attenuation of lesion growth (10 ± 15 mL with reperfusion versus 17 ± 30 mL without reperfusion; P=0.9) in No Mismatch patients. CONCLUSIONS: MRI profiles that are associated with a differential response to reperfusion can be identified with RAPID. This supports the use of automated image analysis software such as RAPID for patient selection in acute stroke trials.

Refining the definition of the malignant profile: insights from the DEFUSE-EPITHET pooled data set.

BACKGROUND AND PURPOSE: To refine the definition of the malignant magnetic resonance imaging profile in acute stroke patients using baseline diffusion-weighted magnetic resonance imaging (DWI) and perfusion-weighted magnetic resonance imaging (PWI) findings from the pooled DEFUSE/EPITHET database. METHODS: Patients presenting with acute stroke within 3 to 6 hours from symptom onset were treated with tissue plasminogen activator or placebo. Baseline and follow-up DWI and PWI images from both studies were reprocessed using the same software program. A receiver operating characteristic curve analysis was used to identify Tmax and DWI volumes that optimally predicted poor outcomes (modified Rankin Scale 5-6) at 90 days in patients who achieved reperfusion. RESULTS: Sixty-five patients achieved reperfusion and 46 did not reperfuse. Receiver operating characteristic analysis identified a PWI (Tmax>8 s) volume of >85 mL as the optimal definition of the malignant profile. Eighty-nine percent of malignant profile patients had poor outcome with reperfusion versus 39% of patients without reperfusion (P=0.02). Parenchymal hematomas occurred more frequently in malignant profile patients who experienced reperfusion versus no reperfusion (67% versus 11%, P<0.01). DWI analysis identified a volume of 80 mL as the best DWI threshold, but this definition was less sensitive than were PWI-based definitions. CONCLUSIONS: Stroke patients likely to suffer parenchymal hemorrhages and poor outcomes following reperfusion can be identified from baseline magnetic resonance imaging findings. The current analysis demonstrates that a PWI threshold (Tmax>8 s) of approximately 100 mL is appropriate for identifying these patients. Exclusion of malignant profile patients from reperfusion therapies may substantially improve the efficacy and safety of reperfusion therapies. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00238537.

Differential associations of cortical and subcortical cerebral atrophy with retinal vascular signs in patients with acute stroke.

BACKGROUND AND PURPOSE: The relationship of cortical and subcortical cerebral atrophy to cerebral microvascular disease is unclear. We aimed to assess the associations of retinal vascular signs with cortical and subcortical atrophy in patients with acute stroke. METHODS: In the Multi-Centre Retinal Stroke Study, 1360 patients with acute stroke admitted to 2 Australian and 1 Singaporean tertiary hospital during 2005 to 2007 underwent neuroimaging and retinal photography. Cortical and subcortical cerebral atrophy were graded based on standard CT scans. A masked assessment of retinal photographs identified focal retinal vascular signs, including retinopathy and retinal arteriolar wall signs (ie, focal arteriolar narrowing, arteriovenous nicking, arteriolar wall light reflex) and measured quantitative signs (retinal arteriolar and venular caliber). RESULTS: After adjusting for age, gender, study site, hypertension, hypercholesterolemia, diabetes, and smoking status, none of the retinal vascular signs assessed were associated with cortical atrophy, whereas retinopathy (OR, 1.9; CI, 1.2 to 3.0) and enhanced arteriolar light reflex (OR, 2.0; CI, 1.2 to 3.2) were significantly associated with subcortical atrophy. CONCLUSIONS: Our finding that certain retinal vascular signs are associated with subcortical but not cortical atrophy, suggests a differential pathophysiology between these 2 cerebral atrophy subtypes and a potential role for small vessel disease underlying subcortical cerebral atrophy.

Retinal microvasculature in acute lacunar stroke: a cross-sectional study.

BACKGROUND: Lacunar stroke accounts for a quarter of cases of acute ischaemic stroke; however, its underlying pathophysiology remains unclear. Our aim was to establish whether there is an association between changes in the retinal microvasculature and lacunar stroke that might provide clues to the pathology of cerebral small vessel disease. METHODS: In this cross-sectional study, we recruited patients who presented with acute stroke at three centres in two countries (Sydney and Melbourne, Australia, and Singapore). Each patient had standardised clinical assessments, retinal photography, and CT or MRI of the brain. Changes in the retinal microvasculature were assessed from retinal photographs by graders who were masked to the patients' clinical details. Lacunar stroke was diagnosed according to a modified version of the TOAST criteria (Treatment of Acute Stroke Trial) or the OCSP criteria (Oxfordshire Community Stroke Project) and by MRI findings. FINDINGS: We recruited 1321 patients aged 19 to 94 years with acute ischaemic stroke; 410 (31%) had lacunar stroke. Patients with acute lacunar stroke were no more likely to have hypertension (p=0.12), diabetes (p=0.51), or hypercholesterolaemia (p=0.91) than were patients with other types of ischaemic stroke. However, patients with lacunar stroke were more likely to have retinal microvessel signs, particularly when stroke subtype was confirmed using diffusion-weighted MRI, than were patients with other stroke subtypes. After adjustment for age, sex, study site, smoking history, hypertension, and diabetes, the patients with lacunar stroke were more likely than those with other stroke subtypes to have microvessel signs, and when stroke subtype was confirmed by diffusion-weighted MRI the odds ratios were: 3.55 (95% CI 1.77-7.12) for focal arteriolar narrowing; 1.96 (1.19-3.24) for arteriovenous nipping; 2.32 (1.42-3.79) for enhanced light reflex of the arteriolar wall; 1.33 (0.74-2.41) for generalised retinal arteriolar narrowing; 1.45 (0.84-2.51) for small retinal arteriole:venule ratio; and 1.35 (0.80-2.26) for retinal venular widening. INTERPRETATION: Our findings suggest that acute lacunar stroke is a manifestation of non-atherothrombotic occlusive small vessel disease, which might have implications for the prevention and treatment of this stroke subtype. FUNDING: National Health and Medical Research Council of Australia; National Medical Research Council of Singapore; Scottish Funding Council; New South Wales Health.