Comparison of short-term outcomes between patients with extracranial carotid and/or intracranial atherosclerotic disease.

OBJECTIVE: To directly compare the 90-day outcomes of patients with symptomatic intracranial atherosclerotic disease (ICAD), extracranial carotid atherosclerotic disease (ECAD), and ICAD with concomitant ECAD. METHODS: From 2017-2021, patients who had (1) a transient ischemic attack or ischemic stroke within 30 days of admission as evaluated by a stroke neurologist and (2) ipsilateral ICAD and/or ECAD were prospectively enrolled. The cohort was divided into three groups: ICAD, ECAD, and ICAD with concomitant ECAD. The primary outcome assessed was 90-day ischemic stroke recurrence. Secondary outcomes included 90-day myocardial infarction (MI), all-cause mortality, and major adverse cardiovascular events (MACE, including cardiovascular death, nonfatal MI, and/or nonfatal ischemic stroke). RESULTS: Of 371 patients included in the analysis, 240 (64.7%) patients had ICAD only, 93 (25.0%) patients had ECAD only, and 38 (10.3%) patients had ICAD with concomitant ECAD. On multivariate time-to-event analysis adjusting for potential confounders and with ICAD as the reference comparator, the risk of 90-day clinical outcomes was highest among patients with ICAD and concomitant ECAD, with adjusted hazard ratios of 4.54 (95% CI=1.45, 14.2; p = 0.006), 9.32 (95% CI=1.58, 54.8; p = 0.014), and 8.52 (95% CI=3.54, 20.5; p < 0.001) for 90-day ischemic stroke, MI, and MACE, respectively. CONCLUSIONS: Patients with ICAD and concomitant ECAD have a poorer prognosis and are at significantly higher risk for 90-day ischemic stroke, MI, and MACE. Further research should focus on the evaluation of coronary atherosclerotic disease and more intensive medical therapy in this population.

Etiologies, mechanisms, and risk factors of ischemic stroke in a young Asian adult cohort.

OBJECTIVES: Risk factors and causes of acute ischemic stroke (AIS) are more diverse in young adults, and traditional stroke classifications may be inadequate. Precise characterisation of AIS is important for guiding management and prognostication. We describe stroke subtypes, risk factors and etiologies for AIS in a young Asian adult population. MATERIALS AND METHODS: Young AIS patients aged 18-50 years admitted to two comprehensive stroke centres from 2020-2022 were included. Stroke etiologies and risk factors were adjudicated using Trial of Org 10172 in Acute Stroke Treatment (TOAST) and International Pediatric Stroke Study (IPSS) risk factors. Potential embolic sources (PES) were identified in a subgroup with embolic stroke of undetermined source (ESUS). These were compared across sex, ethnicities and age groups (18-39 years versus 40-50 years). RESULTS: A total of 276 AIS patients were included, with mean age 43±5.7 years and 70.3% male. Median duration of follow-up was 5 months (IQR: 3-10). The most common TOAST subtypes were small-vessel disease (32.6%) and undetermined etiology (24.6%). IPSS risk factors were identified in 95% of all patients and 90% with undetermined etiology. IPSS risk factors included atherosclerosis (59.5%), cardiac disorders (18.7%), prothrombotic states (12.4%) and arteriopathy (7.7%). In this cohort, 20.3% had ESUS, of which 73.2% had at least one PES, which increased to 84.2% in those <40 years old. CONCLUSIONS: Young adults have diverse risk factors and causes of AIS. IPSS risk factors and ESUS-PES construct are comprehensive classification systems that may better reflect heterogeneous risk factors and etiologies in young stroke patients.

Impact of atrial fibrillation on the treatment effect of bridging thrombolysis in ischemic stroke patients undergoing endovascular thrombectomy: a multicenter international cohort study.

BACKGROUND: The role of bridging intravenous thrombolysis (IVT) before endovascular thrombectomy (EVT) in the treatment of acute ischemic stroke (AIS) remains debatable. Atrial fibrillation (AF) associated strokes may be associated with reduced treatment effect from IVT. This study compares the effect of bridging IVT in AF and non-AF patients. METHODS: This retrospective cohort study comprised anterior circulation large vessel occlusion (LVO) AIS patients receiving EVT alone or bridging IVT plus EVT within 6 hours of symptom onset. Primary outcome was good functional outcome defined as modified Rankin Scale (mRS) 0-2 at 90 days. Secondary outcomes were successful reperfusion defined as expanded Thrombolysis In Cerebral Infarction (eTICI) grading ≥2b flow, symptomatic intracerebral hemorrhage (sICH), and in-hospital mortality. RESULTS: We included 705 patients (314 AF and 391 non-AF patients). The mean age was 68.6 years and 53.9% were male. The odds of good functional outcomes with bridging IVT was higher in the non-AF (adjusted odds ratio (aOR) 2.28, 95% CI 1.06 to 4.91, P=0.035) compared with the AF subgroups (aOR 1.89, 95% CI 0.89 to 4.01, P=0.097). However, this did not constitute a significant effect modification by the presence of AF on bridging IVT (interaction aOR 0.12, 95% CI -1.94 to 2.18, P=0.455). The rate of successful reperfusion, sICH, and mortality were similar between bridging IVT and EVT for both AF and non-AF patients. CONCLUSION: The presence of AF did not modify the treatment effect of bridging IVT. Further individual patient data meta-analysis of randomized trials may shed light on the comparative efficacy of bridging IVT in AF versus non-AF LVO strokes.

Bridging thrombolysis improves survival rates at 90 days compared with direct mechanical thrombectomy alone in acute ischemic stroke due to basilar artery occlusion: a systematic review and meta-analysis of 1096 patients.

BACKGROUND: Mechanical thrombectomy (MT) is an effective treatment for patients with acute ischemic stroke (AIS) from basilar artery occlusion (BAO). OBJECTIVE: To compare the clinical outcomes of MT, with and without bridging intravenous thrombolysis (IVT), in acute BAO through a systematic review and meta-analysis of the current literature. METHODS: Systematic searches of Medline, EMBASE, and Cochrane Central were undertaken on August 1, 2022. Good functional outcome defined as 90-day modified Rankin Scale score 0-2 was the primary outcome measure. Secondary outcome measures were 90-day mortality, successful post-thrombectomy recanalization (modified Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracranial hemorrhage (sICH), and subarachnoid hemorrhage (SAH). RESULTS: Three studies reporting 1096 patients with BAO AIS were included in the meta-analysis. No significant differences in good functional outcome were detected between the two groups (RR=1.28 (95% CI 0.86 to 1.92); p=0.117). However, specifically patients with large artery atherosclerosis (LAA) benefited from bridging IVT (OR=2.52 (95% CI 1.51 to 4.22); p<0.001) with better functional outcomes. There was a significantly lower 90-day mortality rate for patients who underwent bridging IVT compared with MT alone (RR=0.70 (95% CI 0.62 to 0.80); p=0.008). No significant differences were detected in rates of post-treatment recanalization (RR=1.01 (95% CI 0.35 to 2.91); p=0.954), sICH (RR=0.96 (95% CI 0.66 to 1.42); p=0.724), and SAH (RR=0.93 (95% CI 0.31 to 2.83); p=0.563). CONCLUSIONS: In patients with AIS due to BAO, bridging IVT was associated with lower mortality rates at 90 days, compared with direct MT. There were no improved functional outcomes or increased sICH or SAH between both arms, However, patients with LAA benefited from bridging IVT, with better functional outcomes.

Cilostazol for secondary stroke prevention: systematic review and meta-analysis.

BACKGROUND: Stroke is one of the leading causes of death worldwide. Cilostazol, an antiplatelet and phosphodiesterase 3 inhibitor, has not been clearly established for ischaemic stroke use. We aim to determine the efficacy and safety of cilostazol for secondary stroke prevention. METHODS: MEDLINE, EMBASE, Cochrane Library, Web of Science and ClinicalTrials.gov were searched from inception to 25 September 2020, for randomised trials comparing the efficacy and safety of cilostazol monotherapy or dual therapy with another antiplatelet regimen or placebo, in patients with ischaemic stroke. Version 2 of the Cochrane risk-of-bias tool for randomised trials (RoB 2) was used to assess study quality. This meta-analysis was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Eighteen randomised trials comprising 11 429 participants were included in this meta-analysis. Most trials possessed low risk of bias and were of low heterogeneity. Cilostazol significantly reduced the rate of ischaemic stroke recurrence (risk ratio, RR=0.69, 95% CI 0.58 to 0.81), any stroke recurrence (RR=0.64, 95% CI 0.54 to 0.74) and major adverse cardiovascular events (RR=0.67, 95% CI 0.56 to 0.81). Cilostazol did not significantly decrease mortality (RR=0.90, 95% CI 0.64 to 1.25) or increase the rate of good functional outcome (Modified Rankin Scale score of 0-1; RR=1.07, 95% CI 0.95 to 1.19). Cilostazol demonstrated favourable safety profile, significantly reducing the risk of intracranial haemorrhage (RR=0.46, 95% CI 0.31 to 0.68) and major haemorrhagic events (RR=0.49, 95% CI 0.34 to 0.70). CONCLUSIONS: Cilostazol demonstrated superior efficacy and safety profiles compared with traditional antiplatelet regimens such as aspirin and clopidogrel for secondary stroke prevention but does not appear to affect functional outcomes. Future randomised trials can be conducted outside East Asia, or compare cilostazol with a wider range of antiplatelet agents.

Cerebral Venous Thrombosis in Patients with COVID-19 Infection: a Case Series and Systematic Review.

BACKGROUND: There has been increasing reports associating the coronavirus disease 2019 (COVID-19) with thromboembolic phenomenon including ischemic strokes and venous thromboembolism. Cerebral venous thrombosis (CVT) is a rare neurovascular emergency that has been observed in some COVID-19 patients, yet much remains to be learnt of its underlying pathophysiology. OBJECTIVE: We present a case series of local patients with concomitant COVID-19 infection and CVT; and aim to perform a systematic review of known cases in the current literature. METHODS: We describe two patients with concomitant COVID-19 infection and CVT from a nationwide registry in Singapore. We then conducted a literature search in PubMed and Embase using a suitable keyword search strategy from 1st December 2019 to 11th June 2020. All studies reporting CVT in COVID-19 patients were included. RESULTS: Nine studies and 14 COVID-19 patients with CVT were studied. The median age was 43 years (IQR=36-58) and majority had no significant past medical conditions (60.0%). The time taken from onset of COVID-19 symptoms to CVT diagnosis was a median of 7 days (IQR=6-14). CVT was commonly seen in the transverse (75.0%) and sigmoid sinus (50.0%); 33.3% had involvement of the deep venous sinus system. A significant proportion of patients had raised D-dimer (75.0%) and CRP levels (50.0%). Two patients reported presence of antiphospholipid antibodies. Most patients received anticoagulation (91.7%) while overall mortality rate was 45.5%. CONCLUSIONS: The high mortality rate of CVT in COVID-19 infection warrants a high index of suspicion from physicians, and early treatment with anticoagulation should be initiated.

Deep Cerebral Venous Thrombosis Treatment : Endovascular Case using Aspiration and Review of the Various Treatment Modalities.

BACKGROUND: Deep cerebral venous thrombosis (CVT) is an uncommon condition with a high morbidity and mortality. The optimal treatment approach for deep CVT remains uncertain and due to its low prevalence, randomized trials are not feasible. We showcase a straight sinus thrombosis treated with a large bore aspiration and performed a meta-analysis of the available literature to characterize and evaluate the various treatment modalities for patients with deep CVT. METHODS: We conducted a systematic search in PubMed, EMBASE and Ovid Medline using appropriate keywords/MESH terms search strategy. All patients with thrombosis involving the deep venous sinuses were included if treatment records were available. Outcome measures included recanalization of the affected sinus, good functional outcome assessed by a modified Rankin scale (mRS) of 0-2 or reported independent functional outcomes, permanent neurological deficits, further hemorrhage and mortality. RESULTS: A total of 69 studies comprising 120 patients were included in the analysis. Anticoagulation was the most common treatment (85.8%), whilst local intrasinus thrombolysis was performed in 40.0% of the patients and mechanical endovascular modalities were employed in 20.0% of the patients. Recanalization of the occluded sinus was seen in 83.5% of the patients while 62.6% patients achieved good functional outcome. There was considerable morbidity with 60.7% having a permanent neurological deficit, 23.3% having further hemorrhage after admission and 18.6% mortality. In the cohort receiving anticoagulation, 65.3% achieved good outcome but intracranial hemorrhage at presentation was associated with poorer outcome, permanent deficits, further bleeding and mortality. CONCLUSION: Anticoagulation is an effective treatment strategy for deep CVT; however, patients with intracranial hemorrhage at presentation often have poorer outcomes and early endovascular strategies could be considered in this subgroup.

Significant aortic stenosis associated with poorer functional outcomes in patients with acute ischaemic stroke undergoing endovascular therapy.

BACKGROUND AND AIM: Bi-directional feedback mechanisms exist between the heart and brain, which have been implicated in heart failure. We postulate that aortic stenosis may alter cerebral haemodynamics and influence functional outcomes after endovascular thrombectomy for acute ischaemic stroke. We compared clinical characteristics, echocardiographic profile and outcomes in patients with or without aortic stenosis that underwent endovascular thrombectomy for large vessel occlusion acute ischaemic stroke. METHODS: Consecutive acute ischaemic stroke patients with anterior and posterior circulation large vessel occlusion (internal carotid artery, middle cerebral artery and basilar artery) who underwent endovascular thrombectomy were studied. Patients were divided into those with significant aortic stenosis (aortic valve area <1.5 cm2) and without. Univariate and multivariate analyses were employed to compare and determine predictors of functional outcomes measured by modified Rankin scale at three months. RESULTS: We identified 26 (8.5%) patients with significant aortic stenosis. These patients were older (median age 76 (interquartile range 68-84) vs. 67 (interquartile range 56-75) years, p = 0.001), but similar in terms of medical comorbidities and echocardiographic profile. Rates of successful recanalisation (73.1% vs. 78.0%), symptomatic intracranial haemorrhage (7.7% and 7.9%) and mortality (11.5% vs. 12.6%) were similar. Significant aortic stenosis was independently associated with poorer functional outcome (modified Rankin scale >2) at three months (adjusted odds ratio 2.7, 95% confidence interval 1.1-7.5, p = 0.048), after adjusting for age, door-to-puncture times, stroke severity and rates of successful recanalisation. CONCLUSION: In acute ischaemic stroke patients managed with endovascular thrombectomy, significant aortic stenosis is associated with poor functional outcome despite comparable recanalisation rates. Larger cohort studies are needed to explore this relationship further.

Intracranial Artery Calcium Burden Predicts Recurrent Cerebrovascular Events in Transient Ischaemic Attack Patients.

BACKGROUND: Patients with initial transient ischaemic attack (TIA) subsequently have a higher risk of recurrent TIA or acute ischemic stroke (AIS). The role of scoring intracranial arterial calcification (IAC) in predicting the prevalence of stroke remains unclear. We aim to evaluate if radiological CT calcium score measuring IAC burden could predict future ischemic events in a cohort of TIA patients. METHODS: We studied consecutive patients from July 2014 to December 2015 who presented with first episode of TIA. All patients had noncontrasted CT or CT-angiogram of the brain on admission. CT calcium score (cm3) was quantified by measuring calcium deposition in the bilateral internal carotid arteries, middle cerebral arteries, and vertebrobasilar system. Patients were followed up for 2 years and ischemic events for either recurrent TIA or AIS were recorded. We compared patients in terms of clinical profile at presentation and CT calcium score using appropriate univariate and multivariable analyses. RESULTS: Of 156 TIA patients studied, 22% (n = 35) had recurrent TIA or AIS within 2 years of follow-up. On univariate analyses, recurrent TIA/AIS was associated with gender (OR 0.61; 95%CI 0.40-0.95; P = .038), hypertension (mean difference 2.49; 95%CI 1.08-5.75; P = .030) and higher CT calcium score (mean difference 0.84 95%CI 0.16-1.52 P = .016). On multivariable logistic regression, a higher CT calcium score was significantly associated with recurrent TIA/AIS (adjusted OR 1.25 95%CI 1.01-1.55 P = .042). CONCLUSIONS: In TIA patients, higher IAC burden by measurement of a quantitative CT calcium score may be associated with recurrent ischemic events.

Intravenous thrombolysis for acute ischemic stroke in Asia.

Data regarding thrombolysis for acute ischemic stroke in Asia are scarce and only a small percentage of patients are thrombolysed. Clinical trials that led to the recommended dose of intravenously administered tissue plasminogen activator (IV-tPA) included predominantly Caucasian patients. However, the single-arm case-controlled observational studies in Japanese patients suggested the clinical efficacy and safety of low-dose IV-tPA (0.6 mg/kg bodyweight; maximum 60 mg) comparable with standard dose (0.9 mg/kg bodyweight; maximum 90 mg). There has been no randomized clinical trial for determining the dose, efficacy or safety of IV-tPA in Asia. Accordingly, the dose of IV-tPA in Asia remains controversial. Reduced treatment cost, lower symptomatic intracerebral hemorrhage risk and comparable efficacy encouraged many Asian centers to adopt low-dose or even variable-dose IV-tPA regimens. We present the current status of thrombolysis for acute ischemic stroke in Asia.

Diffusion-negative MRI in acute ischemic stroke: a case report.

BACKGROUND: Diffusion-weighted magnetic resonance imaging is a very sensitive tool for the early diagnosis of acute ischemic stroke. This is employed in some stroke centers as the primary screening tool to select patients eligible for thrombolysis. METHODS: We present the case of a 49-years old Chinese man whose diffusion-weighted magnetic resonance imaging performed 12 hours of symptom onset was negative. RESULTS: Although the initial diffusion-weighted magnetic resonance imaging was negative, the imaging repeated after 4 days despite static neurological symptoms and signs, could demonstrate an acute medullary infarction. CONCLUSION: Diffusion-weighted imaging may not be100% sensitive in very early stages, especially in posterior circulation strokes. Our case serves as a reminder that clinical assessment still retains priority until a diagnostic modality offering 100% sensitivity and specificity is discovered.

Validation of transcranial Doppler with CT angiography in cerebral ischaemia: a preliminary pilot study in Singapore.

INTRODUCTION: Transcranial Doppler (TCD) is an established tool for the non-invasive assessment of cerebral blood flow. Since TCD results vary with the skills and experience of the sonographer, it requires validation against contrast angiography. We evaluated the diagnostic accuracy of TCD against computed tomography angiography (CTA) and the feasibility of the latter as an additional screening tool in our acute ischaemic stroke patients. MATERIALS AND METHODS: Our stroke unit manages about 700 patients annually. Acute stroke patients undergo TCD for vascular assessment of major arteries of the circle of Willis. Randomly selected acute stroke patients with significant stenosis on TCD underwent high-resolution cranial CTA with multidetector helical scanner. CTA was performed within 24 hours of TCD and images were interpreted by a neuroradiologist blinded to TCD findings. An independent neurosonologist reevaluated TCD if CTA findings were contradictory. Additional information by either modality was also noted. RESULTS: Fifteen patients (12 men, mean age 61 +/- 15years) with cerebral ischaemia and moderate (>50%) stenosis in > or =1 large intracranial arterial segment on routine TCD were evaluated by CTA. Compared with 21 segments of significant stenosis on CTA, TCD showed 16 true-positive, 3 false-positive and 5 false-negative results (sensitivity: 76.2%, positive predictive value: 84.2%). In 3 cases, TCD showed findings complementary to CTA (real-time embolisation, collateral flow patterns, evidence of distal M2 branch occlusion). CONCLUSION: TCD in our neurovascular laboratory shows a satisfactory agreement with cranial CTA in evaluating patients with cerebral ischaemia. TCD can provide additional real-time dynamic findings complementary to information provided by CTA.

Bridging the gap between primary and specialist care--an integrative model for stroke.

Stroke is a major cause of death and disability in Singapore and many parts of the world. Chronic disease management programmes allow seamless care provision across a spectrum of healthcare facilities and allow appropriate services to be brought to the stroke patient and the family. Randomised controlled trials have provided evidence for efficacious interventions. After the management of acute stroke in a stroke unit, most stable stroke patients can be sent to their family physician for continued treatment and rehabilitation supervision. Disabled stroke survivors may need added home-based services. Suitable community resources will need to be harnessed. Clinic-based stroke nurses may enhance service provision and coordination. Close collaboration between the specialist and family physician would be needed to right-site patients and also allow referrals in either direction where necessary. Barriers to integration can be surmounted by trust and improved communication. Audits would allow monitoring of care provision and quality care enhancement. The Wagner model of chronic care delivery involves self-management support, shared clinical information systems, delivery system redesign, decision support, healthcare organisation and community resources. The key and critical feature is the need for an informed, activated (or motivated) patient, working in collaboration with the specialist and family physician, and a team of nursing and allied healthcare professionals across the continuum of care. The 3-year Integrating Services and Interventions for Stroke (ISIS) project funded by the Ministry of Health will test such an integrative system.

Role of Multimodal Evaluation of Cerebral Hemodynamics in Selecting Patients with Symptomatic Carotid or Middle Cerebral Artery Steno-occlusive Disease for Revascularization.

BACKGROUND: The circle of Willis provides collateral pathways to perfuse the affected vascular territories in patients with severe stenoocclusive disease of major arteries. The collateral perfusion may become insufficient in certain physiological circumstances due to failed vasodilatory reserve and intracranial steal phenomenon, so-called 'Reversed-Robinhood syndrome'. We evaluated cerebral hemodynamics and vasodilatory reserve in patients with symptomatic distal internal carotid (ICA) or middle cerebral artery (MCA) severe steno-occlusive disease. METHODS: Diagnostic transcranial Doppler (TCD) and TCD-monitoring with voluntary breath-holding according to a standard scanning protocol were performed in patients with severe ICA or MCA steno-occlusive disease. The steal phenomenon was detected as transient, spontaneous, or vasodilatory stimuli-induced velocity reductions in affected arteries at the time of velocity increase in normal vessels. Patients with exhausted vasomotor reactivity and intracranial steal phenomenon during breath-holding were further evaluated by (99)technetium(m)-hexamethyl propylene amine oxime single photon emission computed tomography (HMPAO-SPECT) with acetazolamide challenge. RESULTS: Sixteen patients (age 27-74 years, 11 men) fulfilled our TCD criteria for exhausted vasomotor reactivity and intracranial steal phenomenon during the standard vasomotor testing by breath holding. Acetazolamide-challenged HMPAO-SPECT demonstrated significant hypoperfusion in 12 patients in affected arterial territories, suggestive of failed vasodilatory reserve. A breath-holding index of ≤0.3 on TCD was associated with an abnormal HMPAO-SPECT with acetazolamide challenge. TCD findings of a breath holding index of ≤0.3 and intracranial steal during the procedure were determinants of a significant abnormality on HMPAO-SPECT with acetazolamide challenge. CONCLUSION: Multimodal evaluation of cerebral hemodynamics in symptomatic patients with severe steno-occlusive disease of the ICA or MCA is helpful in the identification and quantification of failed vasodilatory reserve. This approach may be useful in selecting patients for possible revascularization procedures.