Recurrent vascular events partially explain association between diabetes and poor prognosis in young ischemic stroke patients.

BACKGROUND AND AIMS: Stroke is the second leading cause of death and third leading cause of disability worldwide. There is an increasing incidence of stroke among the young. In this study, we aimed to identify factors associated with poor long-term prognosis in young stroke patients. METHODS: In this longitudinal observational study, we recruited 147 young ischemic stroke patients within one week of ischemic stroke and followed them up for functional outcome (modified Rankin score (mRS)), recurrent vascular events, and recurrent hospitalisation. Poor function was labelled as mRS score of 3 and above. We performed univariate and multivariable logistic regression analyses to determine factors associated with poor long term functional outcome. RESULTS: At a median follow-up of 7-years, 32 (22%) of the 147 patients had poor functional outcome. In multivariable analyses, diabetes mellitus (OR = 9.01, CI 3.15 to 26.92), was the only independent predictor of poor function. In analyses stratified by diabetic status, recurrent vascular events (OR = 4.47, CI 1.40 to 14.28) were associated with poor functional outcome within young diabetic patients but not in non-diabetic patients. CONCLUSIONS: Our findings suggest that diabetes mellitus affects long-term functional outcome in young ischemic stroke and that its effect is mediated partly by recurrent vascular events. DATA ACCESS STATEMENT: Data obtained from Multi-Centre Retinal study (MCRS), Singapore site. Data cannot be made publicly available due to potentially identifiable research participant information.

National Institutes of Health Stroke Scale: comparison of original and modified versions for Singapore culture.

Introduction: The National Institutes of Health Stroke Scale (NIHSS), originally designed in the United States of America, contains items on dysphasia and dysarthria that are deemed culturally unsuitable for the Singapore context. We compared the error rates of dysphasia objects, dysphasia phrases and dysarthria words between the original and alternative items in a cohort of Singaporean subjects without dysphasia or dysarthria. Methods: In this prospective study, 140 English-speaking Singaporean subjects without impairments of dysphasia or dysarthria had an assessment of NIHSS items 9 and 10 using the original and alternative items. Paired analyses were conducted for comparison of error rates. Results: The error rates were high for four original dysphasia objects (Hammock: 62.9%, Cactus: 38.6%, Feather: 23.6%, Glove: 20.7%) and significantly lower for alternative items (Snail: 5%, Horse: 1.4%, Hanger: 1.4%, Car: 0%) (P < 0.001). For dysphasia phrases and dysarthria words, the error rates were low and there were no differences in error rates between the original and alternative items. Conclusion: There are cultural issues with several dysphasia objects in the original NIHSS as evidenced by the high error rates, which were lowered with more culturally suitable alternatives. This study formed a basis to derive a more suitable version of the NIHSS for English-speaking subjects in Singapore.

Impact of beliefs about medication on the relationship between trust in physician with medication adherence after stroke.

OBJECTIVE: To investigate the relationship between medication adherence, trust in physician and beliefs about medication among stroke survivors. To determine whether beliefs about medication would mediate the relationship between trust in physician and medication adherence. METHODS: A sample of 200 patients with a diagnosis of ischemic stroke or transient ischemic attack (TIA) completed a one-time survey, including the shortened Medication Adherence Report Scale (MARS-5), Beliefs about Medicines Questionnaire (BMQ), and Trust in Physician Scale (TIPS). RESULTS: Our study found that medication adherence was associated with trust in physician (p = 0.019) and four factors of beliefs about medication (BMQ1-Necessity: p < 0.001; BMQ2-Concerns: p = 0.024; BMQ3-Overuse: p = 0.016; BMQ4-Harm: p < 0.001). Furthermore, we found monthly income of survivors moderated the relationship between trust in physician and medication adherence (p = 0.007, CI(95%): [-0.822, -0.132]). CONCLUSIONS: The beliefs about medication mediating the relationship between trust in physician and medication adherence were different based on the stroke survivors' income bracket. PRACTICE IMPLICATIONS: Interventions being developed to improve medication adherence may benefit from improving stroke survivors' trust in physician and addressing their beliefs about medication. In addition, healthcare providers are advised to take monthly income into consideration to effectively address stroke survivors' concerns regarding prescribed medications to mitigate stroke recurrence.

Long-Term Post-Stroke Functional Outcomes: A Comparison of Diabetics and Nondiabetics.

INTRODUCTION: Diabetes mellitus (DM) is known to influence outcomes in the short term following stroke. However, the impact of DM on long-term functional outcomes after stroke is unclear. We compared functional outcomes periodically over 7 years between diabetic and nondiabetic ischemic stroke patients, and investigated the impact of DM on the long-term trajectory of post-stroke functional outcomes. We also studied the influence of age on the diabetes-functional outcome association. METHODS: This is a longitudinal observational cohort study of 802 acute ischemic stroke patients admitted to the Singapore General Hospital from 2005 to 2007. Functional outcomes were assessed using the modified Rankin Scale (mRS) with poor functional outcome defined as mRS ≥3. Follow-up data were determined at 6 months and at median follow-up durations of 29 and 86 months. RESULTS: Among the 802 ischemic stroke patients studied (mean age 64 ± 12 years, male 63%), 42% had DM. In regression analyses adjusting for covariates, diabetic patients were more likely to have poor functional outcomes at 6 months (OR = 2.12, 95% CI: 1.23-3.67) and at median follow-up durations of 29 months (OR = 1.96, 95% CI: 1.37-2.81) and 86 months (OR = 2.27, 95% CI: 1.58-3.25). In addition, age modulated the effect of DM, with younger stroke patients (≤65 years) more likely to have long-term poor functional outcome at the 29-month (p = 0.0179) and 86-month (p = 0.0144) time points. CONCLUSIONS: DM was associated with poor functional outcomes following ischemic stroke in the long term, with the effect remaining consistent throughout the 7-year follow-up period. Age modified the effect of DM in the long term, with an observed increase in risk in the ≤65 age-group but not in the >65 age-group.

Intracranial Large Artery Disease is Independently Associated with Poor Functional Outcome in a Cohort of Ethnic South Asian Ischemic Stroke Patients.

BACKGROUND: Intracranial large artery disease (ICLAD) in ischemic stroke patients is associated with an increased risk for recurrent stroke; however, it is not known if ICLAD influences functional status following stroke. We studied the 6-month functional outcome in south Asian ischemic stroke patients and compared those with and without ICLAD. MATERIALS AND METHODS: This is a prospective cohort study of consecutive south Asian ischemic stroke patients. ICLAD was assessed with transcranial color-coded Doppler ultrasound or magnetic resonance angiography. Functional outcomes were obtained via telephone interviews with poor outcome defined as modified Rankin scale of 3-6. RESULTS: Of 216 ischemic stroke patients studied, 203 (93.9%) had follow-up data, of whom 50.7% (103) had ICLAD. Patients with ICLAD had a higher prevalence of hypertension (P < 0.001), hyperlipidemia (P = 0.047), ischemic heart disease (P = 0.030), and extracranial carotid disease (P = 0.005). A higher proportion of patients with ICLAD had poor functional outcome at 6 months (30.1%) versus those without ICLAD (13.0%) (P = 0.004). After adjusting for age, sex, hypertension, hyperlipidemia, diabetes, ischemic heart disease, atrial fibrillation, extracranial carotid stenosis, and recurrent vascular events, patients with ICLAD were 3.01 (95% confidence interval: 1.35-7.10) times more likely than those without ICLAD to have poor functional outcome. CONCLUSIONS: The presence of ICLAD rendered poorer functional prognosis after stroke. These findings support the specific evaluation of the benefits of known acute stroke treatments such as thrombolysis, as well as investigation of potential novel strategies such as acute stenting.

Changes in Informed Consent Policy and Treatment Delays in Stroke Thrombolysis.

OBJECTIVES: The efficacy of thrombolytic therapy with tissue plasminogen activator (tPA) is highly time dependent. Although clinical guidelines do not recommend written informed consent as it may cause treatment delays, local policy can supersede and require it. From 2014 to 2017, three out of five public hospitals in Singapore changed from written to verbal consent at different time points. We aimed to examine the association of hospital policy changes regarding informed consent on door-to-needle (DTN) times. MATERIALS AND METHODS: Using data from the Singapore Stroke Registry and surveys of local practice, we analyzed data of 915 acute ischemic stroke patients treated with tPA within 3 hours in all public hospitals between July 2014 to Dec 2017. Patient-level DTN times before and after policy changes were examined while adjusting for clinical characteristics, within-hospital clustering, and trends over time. RESULTS: Patient characteristics and stroke severity were similar before and after the policy changes. Overall, the median DTN times decreased from 68 to 53 minutes after the policy changes. After risk adjustment, changing from written to verbal informed consent was associated with a 5.6 minutes reduction (95% CI 1.1-10.0) in DTN times. After the policy changed, the percentage of patients with DTN ≤60 minutes and ≤45 minutes increased from 35.6% to 66.1% (adjusted OR 1.75; 95% CI 1.12-2.74) and 9.3% to 36.0% (adjusted OR 2.42; 95% CI 1.37-4.25), respectively. CONCLUSION: Changing from written to verbal consent is associated with significant improvement in the timeliness of tPA administration in acute ischemic stroke.

Modifiable Factors Associated with Non-Adherence to Secondary Ischaemic Stroke Prevention Strategies.

BACKGROUND: Secondary stroke-prevention strategies proven to reduce stroke recurrence include pharmaceutical agents and lifestyle modifications. AIMS: We aimed to study factors associated with adherence to medications and lifestyle modifications amongst ischaemic stroke and transient ischaemic attack (TIA) patients. METHODS: In a prospective cohort study, we surveyed 200 outpatients attending stroke clinic at a Singaporean tertiary hospital. We determined medication knowledge and lifestyle modification adherence through direct questioning. We also administered the Beliefs About Medicines Questionnaire, Trust in Physician Scale, Patient Health Questionnaire and Hospital Anxiety and Depression Scale. Multivariable logistic regression models were used to identify factors associated with adherence. RESULTS: The rates of adherence to medications, smoking cessation, dietary modification, and exercise were 52.3%, 71.0%, 80.0% and 78.5% respectively. Subjects who lacked medication knowledge (OR=3.47; 95% CI=1.55-7.74) or possessed negative medication beliefs (OR=1.20; 95% CI=0.72-0.96) were less likely to be adherent to medications. TIA as an index event (OR=5.04; 95% CI=1.39-18.32), younger age (OR=1.04; 95% CI=1.01-1.08) and higher income (OR=2.40; 95% CI=1.09-5.25) were also associated with medication non-adherence. There were no associations between adherence to medications and lifestyle modifications. Dietary adherence was independently associated with exercise adherence (OR=17.2; 95% CI=3.21-92.22). CONCLUSIONS: Our findings of suboptimal adherence to medications and lifestyle modifications show that many stroke patients are not benefitting from proven secondary stroke prevention strategies. We identified medication knowledge and medication beliefs as potential target areas for studies to improve medication adherence.

Emergency medical services use and its association with acute ischaemic stroke evaluation and treatment in Singapore.

BACKGROUND: Emergency medical services (EMS) is a critical link in the chain of stroke survival. We aimed to assess EMS use for stroke in Singapore, identify characteristics associated with EMS use and the association of EMS use with stroke evaluation and treatment. METHODS: The Singapore Stroke Registry combines nationwide EMS and public hospital data for stroke cases in Singapore. Multivariate regressions with the generalised estimating equations were performed to examine the association between EMS use and timely stroke evaluation and treatment. RESULTS: Of 3555 acute ischaemic patients with symptom onset within 24 hours admitted to all five public hospitals between 2015 and 2016, 68% arrived via EMS. Patients who used EMS were older, were less likely to be female, had higher stroke severity by National Institute of Health Stroke Scale and had a higher prevalence of atrial fibrillation or peripheral arterial disease. Patients transported by EMS were more likely to receive rapid evaluation (door-to-imaging time ≤25 min 34.3% vs 11.1%, OR=2.74 (95% CI 1.40 to 5.38)) and were more likely to receive intravenous tissue plasminogen activator (tPA, 22.8% vs 4.6%, OR=4.61 (95% CI 3.52 to 6.03)). Among patients treated with tPA, patients who arrived via EMS were more likely to receive timely treatment than self-transported patients (door-to-needle time ≤60 min 52.6% vs 29.4%, OR=2.58 (95% CI 1.35 to 4.92)). CONCLUSIONS: EMS use is associated with timely stroke evaluation and treatment in Singapore. Seamless EMS-Hospital stroke pathways and targeted public campaigns to advocate for appropriate EMS use have the potential to improve acute stroke care.

Wake-up Stroke and Onset-to-door Duration Delays: Potential Future Indications for Reperfusion Therapy.

INTRODUCTION: There is limited utilisation of acute stroke reperfusion treatments which have narrow therapeutic windows, with delayed hospital presentation being a major limiting factor in Singapore. Most patients who wake up with symptoms are ineligible for reperfusion treatments as duration from onset time is not known. We studied the profile of wake-up strokes, onset-to-door duration and their associated factors among ischaemic stroke patients in the context of potential new treatments. MATERIALS AND METHODS: This is an observational study of consecutive ischaemic stroke patients presenting within 2 weeks of symptom onset to the Singapore General Hospital in 2012. RESULTS: Of the 642 ischaemic stroke patients studied, 33% of the cases were wake-up strokes [median age 64 years, 88%<80 years; median NIHSS score 4, 98%<20]. The median onset-to-door duration was 14.3 hours (Interquartile range, 4.8 to 38.2 hours), 20% of them arrived <3.5 hours (considering eligibility for intravenous alteplase in the proven 4.5 hours window accounting for a one hour door-to-needle duration), 14%: ≥3.5 to <8 hours, 11%: ≥8 to <12 hours, and 56%: ≥12 hours. Most patients with known stroke risk factors including atrial fibrillation (66%), hypertension (78%) and prior stroke (81%) presented beyond 3.5 hours. CONCLUSION: The one- third proportion of wake-up stroke in this cohort and low prevalence of relative contraindications suggest this is a promising group for emerging thrombolysis indications. With the majority of patients presenting after 8 hours, widening of the therapeutic window with new potential reperfusion treatments would not appreciably increase treatment utilisation. This study reaffirms the urgent need for public education to improve stroke awareness in Singapore.

Circulating microRNAs as biomarkers of acute stroke.

MicroRNAs have been identified as key regulators of gene expression and thus their potential in disease diagnostics, prognosis and therapy is being actively pursued. Deregulation of microRNAs in cerebral pathogenesis has been reported to a limited extent in both animal models and human. Due to the complexity of the pathology, identifying stroke specific microRNAs has been a challenge. This study shows that microRNA profiles reflect not only the temporal progression of stroke but also the specific etiologies. A panel of 32 microRNAs, which could differentiate stroke etiologies during acute phase was identified and verified using a customized TaqMan Low Density Array (TLDA). Furthermore we also found 5 microRNAs, miR-125b-2*, -27a*, -422a, -488 and -627 to be consistently altered in acute stroke irrespective of age or severity or confounding metabolic complications. Differential expression of these 5 microRNAs was also observed in rat stroke models. Hence, their specificity to the stroke pathology emphasizes the possibility of developing these microRNAs into accurate and useful tools for diagnosis of stroke.

Associations of retinal microvascular signs and intracranial large artery disease.

BACKGROUND AND PURPOSE: Intracranial large artery disease (ICLAD) is a major cause of ischemic stroke. Retinal microvascular changes are associated with stroke, including small vessel cerebral disease and extracranial carotid disease. We examined the relationship between ICLAD and retinal microvascular changes. METHODS: This is a prospective cohort of 802 acute ischemic stroke patients. Retinal changes were assessed from photographs by graders masked to clinical data. ICLAD was evaluated using prespecified criteria. RESULTS: ICLAD was not associated with ipsilateral retinal arteriolar/venular caliber, focal arteriolar narrowing, or arteriovenous nicking. Severe enhanced arteriolar light reflex was independently associated with any ICLAD (P=0.006) and severe ICLAD (P<0.001). CONCLUSIONS: Enhanced arteriolar light reflex, but not retinal vessel caliber, was related to ICLAD. These data suggest that retinal microvascular signs have specific associations with large cerebral vessel disease.

Timing of arrival to a tertiary hospital after acute ischaemic stroke - A follow-up survey 5 years later.

INTRODUCTION: Intravenous tissue plasminogen activator (tPA) within 3 hours of stroke onset is a licensed proven therapy for ischaemic stroke, with recent trial data showing benefit up to 4.5 hours. We previously published in this journal data of a survey conducted in 2004 showing only 9% of ischaemic stroke patients presenting to the Singapore General Hospital (SGH) arrived within 2 hours of onset. We aimed to determine whether the problem of delayed hospital arrival persists in 2009 and to establish the impact of widening the time window for intravenous tPA to 4.5 hours. MATERIALS AND METHODS: We prospectively surveyed consecutive ischaemic stroke patients admitted to the SGH from 9th March to 30th April 2009. Patients and/or relatives were interviewed with a standardised form similar to the 2004 survey. RESULTS: Among the 146 ischaemic stroke patients surveyed (median age 67 years, 59% male, median NIHSS score 2), 6% presented to SGH within 2 hours and 15% within 3.5 hours of onset. Median time from stroke onset to hospital arrival was 1245 minutes (20.75 hours). Pre-hospital consultation was significantly associated with hospital arrival after 2 hours from onset. Main reasons cited for delay were not realising the gravity of symptoms (31%) and not recognising them as stroke (27%). CONCLUSION: Delayed arrival to SGH following acute ischaemic stroke remains a problem in 2009. This confirms the lack of stroke awareness in Singapore and highlights the need for public stroke education. Furthermore, these data confirm that widening the time window for intravenous tPA treatment to 4.5 hours at SGH will increase its utilisation.

Metabolic syndrome is associated with intracranial large artery disease among ethnic Chinese patients with stroke.

BACKGROUND: The association of metabolic syndrome (MetS) and intracranial large artery disease (ICLAD) has been described, but only in cohorts of ethnic Korean patients with stroke. We investigated the relationship of MetS and ICLAD among ethnic Chinese patients. METHODS: This is a prospective study of consecutive ethnic Chinese patients with acute ischemic stroke living in Singapore. ICLAD was diagnosed on transcranial color-coded Doppler or magnetic resonance angiography. RESULTS: Among the 135 patients studied, the frequency of MetS was higher among patients with ICLAD (39% v 16%, P = .003). This association was independent of age, hypertension, and diabetes (P = .003), and individual MetS criteria (P = .004). The prevalence of ICLAD positively correlated with the number of MetS criteria fulfilled (P = .021). CONCLUSIONS: Our findings of an association between MetS and ICLAD among ethnic Chinese patients with stroke concur with findings among ethnic Korean patients. This validation provides a basis for further investigation into the pathophysiologic link between MetS and ICLAD.

Ethnic South Asian ischaemic stroke patients have a higher prevalence of a family history of vascular disease compared to age, gender and diabetes-matched ethnic Chinese subjects.

Family history is a known non-modifiable risk factor of stroke. We aimed to compare the frequency of a family history of vascular disease between ethnic South Asian and Chinese stroke patients. We studied consecutive ethnic South Asian and Chinese ischaemic stroke patients matched for age, gender and presence of diabetes. Among the 152 matched pairs, ethnic South Asian ischaemic stroke patients had a higher frequency of vascular family history (IHD OR 3.465 p<0.001; CVD OR 1.754 p=0.059; and either IHD or CVD OR 2.169 p=0.003) compared to matched ethnic Chinese patients, independent of past IHD history and stroke subtype. In the ethnic South Asian cohort, patients < or = 60 years old had a higher frequency of a family history of IHD (37% vs 13%, p<0.001), CVD (34% vs 15%, p=0.005) and either IHD or CVD (52% vs 25%, p<0.001) compared to those >60 years. Family history of vascular disease is common among ethnic South Asian ischaemic stroke patients, particularly among those < or = 60 years old. We postulate that the higher frequency of a vascular family history among ethnic South Asians compared to ethnic Chinese may be explained by genetic, environmental and lifestyle influences, or interactions between these factors.

Arterial stiffness is associated with intracranial large artery disease among ethnic Chinese and South Asian ischemic stroke patients.

OBJECTIVE: Intracranial large artery disease (ICLAD) is a common stroke subtype that carries a poor prognosis. We studied the association of arterial stiffness, a recognized risk factor for atherosclerosis and ICLAD among ethnic Chinese and South Asian ischemic stroke patients. METHODS: In this prospective study, we recruited consecutive ischemic stroke patients of Chinese and South Asian ethnicity. ICLAD was assessed by transcranial color-coded Doppler or magnetic resonance angiographic studies. Arterial stiffness was measured by carotid-femoral pulse wave velocity (cPWV). RESULTS: Among the 268 patients studied, the prevalence of ICLAD was 54% and median cPWV was 11.4 m/s (interquartile range 9.0-13.6 m/s). Patients with ICLAD had higher cPWV compared with those without (median 11.7 vs. 11.0 m/s, P = 0.015). In multivariate analysis, patients with ICLAD were significantly more likely to have cPWV measurements in the highest quintile (>14.1 m/s) compared with patients without ICLAD independently of other covariates [odds ratio 2.21, P = 0.038]. CONCLUSION: This study revealed a novel association between arterial stiffness and ICLAD among ischemic stroke patients. The findings suggest that arterial stiffness may be involved in the pathophysiology of ICLAD. Future studies should investigate the effects of reducing arterial stiffness among stroke patients with ICLAD.

Serum erythrocyte sedimentation rate is higher among ethnic South Asian compared to ethnic Chinese ischemic stroke patients. Is this attributable to metabolic syndrome or central obesity?

Inflammation, a vascular risk factor, is more pronounced among ethnic South Asians compared to ethnic Chinese in the general population. We compared serum erythrocyte sedimentation rate (ESR) levels between ethnic South Asian and Chinese acute ischemic stroke patients, and further investigated if metabolic syndrome or central obesity could account for any difference detected. We prospectively recruited consecutive ischemic stroke patients within seven days of onset. Measurement of serum ESR was performed within two days of admission. Median serum ESR was higher among the 55 ethnic South Asian (16 mm/h IQR 3-35) compared to the 165 ethnic Chinese patients (9 mm/h IQR 4-19), p=0.004). Serum ESR was correlated with age. Higher serum ESR was associated with female gender, non-smokers, patients with central obesity and low high-density lipoprotein (HDL) cholesterol. Using regression analysis, South Asian ethnicity remained significantly associated with serum ESR, independent of age, gender, smoking status, metabolic syndrome, central obesity and low HDL. Ethnic South Asian ischemic stroke patients have a higher inflammatory state compared to ethnic Chinese patients. As the higher inflammatory state is independent of demographic and risk factors, we propose an underlying genetic or cultural basis for the ethnic difference.

Concomitant coronary artery disease among Asian ischaemic stroke patients.

INTRODUCTION: Coronary artery disease (CAD) is the leading cause of death following ischaemic stroke. We aimed to study the prevalence and associations of concomitant CAD among ischaemic stroke patients in Singapore. MATERIALS AND METHODS: We prospectively studied 2686 consecutive Asian ischaemic stroke patients. RESULTS: CAD was prevalent among 24% of the study patients. Older age, hypertension, diabetes, hyperlipidaemia, atrial fibrillation, large stroke and South Asian ethnicity were independently associated with CAD. CONCLUSIONS: The variables found to be associated with CAD are known atherosclerotic risk factors (older age, hypertension, diabetes, hyperlipidaemia) or associations of cardioembolic stroke (atrial fibrillation, large stroke). The over-representation of South Asians with concomitant CAD is consistent with the high burden of CAD in this ethnic group.