Long-term colchicine for the prevention of vascular recurrent events in non-cardioembolic stroke (CONVINCE): a randomised controlled trial.

BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.

Platelet Biomarkers in Patients with Atherosclerotic Extracranial Carotid Artery Stenosis: A Systematic Review.

OBJECTIVE: The aim was to enhance understanding of the role of platelet biomarkers in the pathogenesis of vascular events and risk stratifying patients with asymptomatic or symptomatic atherosclerotic carotid stenosis. DATA SOURCES: Systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. REVIEW METHODS: A systematic review collated data from 1975 to 2020 on ex vivo platelet activation and platelet function/reactivity in patients with atherosclerotic carotid stenosis. RESULTS: Forty-three studies met the inclusion criteria; the majority included patients on antiplatelet therapy. Five studies showed increased platelet biomarkers in patients with ≥ 30% asymptomatic carotid stenosis (ACS) vs. controls, with one neutral study. Preliminary data from one study suggested that quantification of "coated platelets" in combination with stenosis severity may aid risk stratification in patients with ≥ 50% - 99% ACS. Platelets were excessively activated in patients with ≥ 30% symptomatic carotid stenosis (SCS) vs. controls (≥ 11 positive studies and one neutral study). Antiplatelet-High on Treatment Platelet Reactivity (HTPR), previously called "antiplatelet resistance", was observed in 23% - 57% of patients on aspirin, with clopidogrel-HTPR in 25% - 100% of patients with ≥ 50% - 99% ACS. Aspirin-HTPR was noted in 9.5% - 64% and clopidogrel-HTPR in 0 - 83% of patients with ≥ 50% SCS. However, the data do not currently support the use of ex vivo platelet function/reactivity testing to tailor antiplatelet therapy outside of a research setting. Platelets are excessively activated (n = 5), with increased platelet counts (n = 3) in recently symptomatic vs. asymptomatic patients, including those without micro-emboli on transcranial Doppler (TCD) monitoring (n = 2). Most available studies (n = 7) showed that platelets become more reactive or activated following carotid endarterectomy or stenting, either as an acute phase response to intervention or peri-procedural treatment. CONCLUSION: Platelets are excessively activated in patients with carotid stenosis vs. controls, in recently symptomatic vs. asymptomatic patients, and may become activated/hyper-reactive following carotid interventions despite commonly prescribed antiplatelet regimens. Further prospective multicentre studies are required to determine whether models combining clinical, neurovascular imaging, and platelet biomarker data can facilitate optimised antiplatelet therapy in individual patients with carotid stenosis.

Stent Design, Restenosis and Recurrent Stroke After Carotid Artery Stenting in the International Carotid Stenting Study.

Background and Purpose- Open-cell carotid artery stents are associated with a higher peri-procedural stroke risk than closed-cell stents. However, the effect of stent design on long-term durability of carotid artery stenting (CAS) is unknown. We compared the medium- to long-term risk of restenosis and ipsilateral stroke between patients treated with open-cell stents versus closed-cell stents in the ICSS (International Carotid Stenting Study). Methods- Patients with symptomatic carotid stenosis were randomized to CAS or endarterectomy and followed with duplex ultrasound for a median of 4.0 years. We analyzed data from patients with completed CAS procedures, known stent design, and available ultrasound follow-up. The primary outcome, moderate or higher restenosis (≥50%) was defined as a peak systolic velocity of >1.3 m/s on ultrasound or occlusion of the treated internal carotid artery and analyzed with interval-censored models. Results- Eight hundred fifty-five patients were allocated to CAS. Seven hundred fourteen patients with completed CAS and known stent design were included in the current analysis. Of these, 352 were treated with open-cell and 362 with closed-cell stents. Moderate or higher restenosis occurred significantly less frequently in patients treated with open-cell (n=113) than closed-cell stents (n=154; 5-year risks were 35.5% versus 46.0%; unadjusted hazard ratio, 0.68; 95% CI, 0.53-0.88). There was no significant difference in the risk of severe restenosis (≥70%) after open-cell stenting (n=27) versus closed-cell stenting (n=43; 5-year risks, 8.6% versus 12.7%; unadjusted hazard ratio, 0.63; 95% CI, 0.37-1.05). The risk of ipsilateral stroke beyond 30 days after treatment was similar with open-cell and closed-cell stents (hazard ratio, 0.78; 95% CI, 0.35-1.75). Conclusions- Moderate or higher restenosis after CAS occurred less frequently in patients treated with open-cell stents than closed-cell stents. However, both stent designs were equally effective at preventing recurrent stroke during follow-up. Clinical Trial Registration- URL: http://www.isrctn.com/. Unique identifier: ISRCTN25337470.

Optimal Antiplatelet Therapy in Moderate to Severe Asymptomatic and Symptomatic Carotid Stenosis: A Comprehensive Review of the Literature.

OBJECTIVES: Carotid stenosis patients are at risk of vascular events despite antiplatelet therapy. Data on prescribed antiplatelet regimens have not been comprehensively collated from trials to guide optimal therapy in this population. METHODS: This review was conducted in line with the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Medline, Ovid, Embase, Web of Science, and Google Scholar from 1988 to 2018 were searched using the search terms "carotid stenosis", "asymptomatic", "symptomatic", "antiplatelet", and "anti-platelet" to identify randomised trials in patients with asymptomatic or symptomatic extracranial moderate-severe carotid stenosis on any form of antiplatelet therapy in which vascular events and pre specified composite outcome events were reported. RESULTS: Twenty-five studies were judged eligible for inclusion. Data from one randomised controlled trial showed no significant difference in benefit with aspirin versus placebo in asymptomatic carotid stenosis, but it is still reasonable to recommend aspirin (81-325 mg daily) for prevention of vascular events in these patients. Low to medium dose aspirin (81-325 mg daily) is superior to higher doses (>650 mg daily) at preventing recurrent vascular events in patients undergoing endarterectomy. Data from endovascular treatment (EVT) trials support peri-procedural treatment of asymptomatic and symptomatic patients with 81-325 mg of aspirin daily. The use of peri-procedural aspirin-clopidogrel in patients undergoing EVT is based on one pilot trial, but appears safe. Short-term aspirin-dipyridamole or aspirin-clopidogrel treatments are equally effective at reducing micro-embolic signals on transcranial Doppler ultrasound in patients with ≥50% symptomatic carotid stenosis. There is insufficient evidence to recommend routine aspirin-clopidogrel combination therapy to reduce the risk of recurrent clinical ischaemic events in patients with symptomatic moderate-severe carotid stenosis. CONCLUSIONS: This comprehensive review outlines an evidence based approach to antiplatelet therapy in carotid stenosis patients. Future trials should randomise such patients to receive different antiplatelet regimens to assess their efficacy and safety and to optimise peri-procedural and long-term preventive treatment in this patient cohort.

Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis.

Background and Purpose- Scarce data indicate that statin pretreatment (SP) in patients with acute cerebral ischemia because of large artery atherosclerosis may be related to lower risk of recurrent stroke because of a decreased incidence of microembolic signals (MES) during transcranial Doppler monitoring. Methods- We performed a systematic review and meta-analysis of available observational studies reporting MES presence/absence or MES burden, categorized according to SP status, in patients with acute cerebral ischemia because of symptomatic (≥50%) large artery atherosclerosis. In studies with partially-published data, authors were contacted for previously unpublished information. We also performed a sensitivity analysis of studies with data on MES burden categorized according to SP status, and an additional subgroup analysis in patients receiving higher-dose SP (atorvastatin 80 mg or rosuvastatin 40 mg daily). Results- Seven eligible study protocols were identified (610 patients, 54% with SP). SP was associated with a reduced risk of MES detection during transcranial Doppler monitoring (risk ratio=0.67; 95% CI, 0.45-0.98), with substantial heterogeneity between studies ( I2=52%). In studies reporting MES burden (n=4), a significantly lower number of MES were identified in patients with compared with those without SP (mean difference=-0.92; 95% CI, -1.64 to -0.19), with no evidence of heterogeneity between studies ( I2=49%). Subgroup analysis revealed that higher-dose SP reduced the risk of detecting MES (risk ratio=0.23; 95% CI, 0.06-0.88), with no evidence of heterogeneity between studies ( I2=0%). Conclusions- SP seems to be associated with a lower incidence and burden of MES in patients with acute cerebral ischemia because of large artery atherosclerosis.

Dolichoectasia and Small Vessel Disease in Young Patients With Transient Ischemic Attack and Stroke.

BACKGROUND AND PURPOSE: We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients. METHODS: We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young (<55 years) transient ischemic attack/stroke patients in whom detailed clinical data and brain MRI were obtained, and stroke subtyping with TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment) was performed. RESULTS: Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09-1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59-2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13-1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions, P=0.065; 29.1% versus 16.5% for old lesions, P<0.001), infarct location in the brain stem (12.4% versus 6.9%, P<0.001), and in white matter (27.8% versus 21.1%, P=0.001). Microbleeds (16.3% versus 4.7%, P=0.001), higher grades of white matter hyperintensities (P<0.001), and small vessel disease subtype (18.1% versus 12.4%, overall P for differences in TOAST (P=0.018) were more often present in patients with dolichoectasia. CONCLUSIONS: Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Patent Foramen Ovale and Cryptogenic Strokes in the Stroke in Young Fabry Patients Study.

BACKGROUND AND PURPOSE: A patent foramen ovale (PFO) is disproportionately prevalent in patients with cryptogenic stroke. Without alternative explanations, it is frequently considered to be causative. A detailed stratification of these patients may improve the identification of incidental PFO. METHODS: We investigated the PFO prevalence in 3497 transient ischemic attack and ischemic stroke patients aged 18 to 55 years in the prospective multicenter SIFAP1 study (Stroke in Young Fabry Patients 1) using the ASCO classification. Patients without an obvious cause for transient ischemic attack/stroke (ASCO 0) were divided into subgroups with and without vascular risk factors (ASCO 0+ and 0-). In addition, we looked for PFO-related magnetic resonance imaging lesion patterns. RESULTS: PFO was identified in 25% of patients. Twenty percent of patients with a definite or probable cause of transient ischemic attack/stroke (≥1 grade 1 or 2 ASCO criterion; n=1769) had a PFO compared with 29% of cryptogenic stroke patients (ASCO 0 and 3; n=1728; P<0,001); subdivision of cryptogenic strokes revealed a PFO in 24% of 978 ASCO 3 patients (n.s. versus ASCO 1 and 2) and a higher prevalence of 36% in 750 ASCO 0 cases (P<0.001 versus ASCO 3 and versus ASCO 1 and 2). PFO was more commonly observed in ASCO 0- (n=271) than in ASCO 0+ patients (n=479; 48 versus 29%; P<0.001). There was no PFO-associated magnetic resonance imaging lesion pattern. CONCLUSIONS: Cryptogenic stroke patients demonstrate a heterogeneous PFO prevalence. Even in case of less conclusive diseases like nonstenotic arteriosclerosis, patients should preferentially be considered to have a non-PFO-mediated stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Validation of two risk-prediction models for recurrent falls in the first year after stroke: a prospective cohort study.

Background: several multivariable models have been derived to predict post-stroke falls. These require validation before integration into clinical practice. The aim of this study was to externally validate two prediction models for recurrent falls in the first year post-stroke using an Irish prospective cohort study. Methodology: stroke patients with planned home-discharges from five hospitals were recruited. Falls were recorded with monthly diaries and interviews 6 and 12 months post-discharge. Predictors for falls included in two risk-prediction models were assessed at discharge. Participants were classified into risk groups using these models. Model 1, incorporating inpatient falls history and balance, had a 6-month outcome. Model 2, incorporating inpatient near-falls history and upper limb function, had a 12-month outcome. Measures of calibration, discrimination (area under the curve (AUC)) and clinical utility (sensitivity/specificity) were calculated. Results: 128 participants (mean age = 68.6 years, SD = 13.3) were recruited. The fall status of 117 and 110 participants was available at 6 and 12 months, respectively. Seventeen and 28 participants experienced recurrent falls by these respective time points. Model 1 achieved an AUC = 0.56 (95% CI 0.46-0.67), sensitivity = 18.8% and specificity = 93.6%. Model 2 achieved AUC = 0.55 (95% CI 0.44-0.66), sensitivity = 51.9% and specificity = 58.7%. Model 1 showed no significant difference between predicted and observed events (risk ratio (RR) = 0.87, 95% CI 0.16-4.62). In contrast, model 2 significantly over-predicted fall events in the validation cohort (RR = 1.61, 95% CI 1.04-2.48). Conclusions: both models showed poor discrimination for predicting recurrent falls. A further large prospective cohort study would be required to derive a clinically useful falls-risk prediction model for a similar population.

Cervical artery dissection in young adults in the stroke in young Fabry patients (sifap1) study.

BACKGROUND: Patients with carotid artery dissection (CAD) have been reported to have different vascular risk factor profiles and clinical outcomes to those with vertebral artery dissection (VAD). However, there are limited data from recent, large international studies comparing risk factors and clinical features in patients with cervical artery dissection (CeAD) with other TIA or ischemic stroke (IS) patients of similar age and sex. METHODS: We analysed demographic, clinical and risk factor profiles in TIA and IS patients ≤55 years of age with and without CeAD in the large European, multi-centre, Stroke In young FAbry Patients 1 (sifap1) study. Patients were further categorised according to age (younger: 18-44 years; middle-aged: 45-55 years), sex, and site of dissection. RESULTS: Data on the presence of dissection were available in 4,208 TIA and IS patients of whom 439 (10.4%) had CeAD: 196 (50.1%) had CAD, 195 (49.9%) had VAD, and 48 had multiple artery dissections or no information regarding the dissected artery. The prevalence of CAD was higher in women than in men (5.9 vs. 3.8%, p < 0.01), whereas the prevalence of VAD was similar in women and men (4.6 vs. 4.7%, n.s.). Patients with VAD were younger than patients with CAD (median = 41 years (IQR = 35-47 years) versus median = 45 years (IQR = 39-49 years); p < 0.01). At stroke onset, about twice as many patients with either CAD (54.0 vs. 23.1%, p < 0.001) or VAD (63.4 vs. 36.6%, p < 0.001) had headache than patients without CeAD and stroke in the anterior or posterior circulation, respectively. Compared to patients without CeAD, hypertension, concomitant cardiovascular diseases and a patent foramen ovale were significantly less prevalent in both CAD and VAD patients, whereas tobacco smoking, physical inactivity, obesity and a family history of cerebrovascular diseases were found less frequently in CAD patients, but not in VAD patients. A history of migraine was observed at a similar frequency in patients with CAD (31%), VAD (27.8%) and in those without CeAD (25.8%). CONCLUSIONS: We identified clinical features and risk factor profiles that are specific to young patients with CeAD, and to subgroups with either CAD or VAD compared to patients without CeAD. Therefore, our data support the concept that certain vascular risk factors differentially affect the risk of CAD and VAD.

Platelet function testing in transient ischaemic attack and ischaemic stroke: A comprehensive systematic review of the literature.

The majority of patients with ischaemic cerebrovascular disease (CVD) are not protected from further vascular events with antiplatelet therapy. Measurement of inhibition of platelet function ex vivo on antiplatelet therapy, using laboratory tests that correlate with the clinical effectiveness of these agents, would potentially enable physicians to tailor antiplatelet therapy to suit individuals. A systematic review of the literature was performed to collate all available data on ex vivo platelet function/reactivity in CVD patients, especially those treated with aspirin, dipyridamole or clopidogrel. Particular emphasis was paid to information from commonly available whole blood platelet function analysers (PFA-100®, VerifyNow® and Multiplate®). Data on pharmacogenetic mechanisms potentially influencing high on-treatment platelet reactivity (HTPR) on antiplatelet therapy in CVD were reviewed. Two-hundred forty-nine potentially relevant articles were identified; 93 manuscripts met criteria for inclusion. The prevalence of ex vivo HTPR in CVD varies between 3-62% with aspirin monotherapy, 8-61% with clopidogrel monotherapy and 56-59% when dipyridamole is added to aspirin in the early, subacute or late phases after TIA/stroke onset. The prevalence of HTPR on aspirin was higher on the PFA-100 than on the VerifyNow in one study (p < 0.001). Furthermore, the prevalence of HTPR on aspirin was lower when one used 'novel longitudinal' rather than 'cross-sectional, case-control' definitions of HTPR on the PFA early after TIA or stroke (p = 0.003; 1 study). Studies assessing the influence of genetic polymorphisms on HTPR in CVD patients are limited, and need validation in large multicentre studies. Available data illustrate that an important proportion of CVD patients have ex vivo HTPR on their prescribed antiplatelet regimen, and that the prevalence varies depending on the definition and assay used. Large, adequately-sized, prospective multicentre collaborative studies are urgently needed to determine whether comprehensive assessment of HTPR at high and low shear stress with a range of user-friendly whole blood platelet function testing platforms, in conjunction with pharmacogenetic data, improves our ability to predict the risk of recurrent vascular events in CVD patients, and thus enhance secondary prevention following TIA or ischaemic stroke.

Prevalence of ex vivo high on-treatment platelet reactivity on antiplatelet therapy after transient ischemic attack or ischemic stroke on the PFA-100(®) and VerifyNow(®).

BACKGROUND: The prevalence of ex vivo high on-treatment platelet reactivity (HTPR) to commonly prescribed antiplatelet regimens after transient ischemic attack (TIA) or ischemic stroke is uncertain. METHODS: Platelet function inhibition was simultaneously assessed with modified light transmission aggregometry (VerifyNow; Accumetrics Inc, San Diego, CA) and with a moderately high shear stress platelet function analyzer (PFA-100; Siemens Medical Solutions USA, Inc, Malvern, PA) in a pilot, cross-sectional study of TIA or ischemic stroke patients. Patients were assessed on aspirin-dipyridamole combination therapy (n = 51) or clopidogrel monotherapy (n = 25). RESULTS: On the VerifyNow, HTPR on aspirin was identified in 4 of 51 patients (8%) on aspirin-dipyridamole combination therapy (≥ 550 aspirin reaction units on the aspirin cartridge). Eleven of 25 (44%) patients had HTPR on clopidogrel (≥ 194 P2Y12 reaction units on the P2Y12 cartridge). On the PFA-100, 21 of 51 patients (41%) on aspirin-dipyridamole combination therapy had HTPR on the collagen-epinephrine (C-EPI) cartridge. Twenty-three of 25 patients (92%) on clopidogrel had HTPR on the collagen-adenosine diphosphate (C-ADP) cartridge. The proportion of patients with antiplatelet HTPR was lower on the VerifyNow than PFA-100 in patients on both regimens (P < .001). CONCLUSIONS: The prevalence of ex vivo antiplatelet HTPR after TIA or ischemic stroke is markedly influenced by the method used to assess platelet reactivity. The PFA-100 C-ADP cartridge is not sensitive at detecting the antiplatelet effects of clopidogrel ex vivo. Larger prospective studies with the VerifyNow and with the PFA-100 C-EPI and recently released Innovance PFA P2Y cartridges (Siemens Medical Solutions USA, Inc) in addition to newer tests of platelet function are warranted to assess whether platelet function monitoring predicts clinical outcome in ischemic cerebrovascular disease.

Frequency of inter-specialty consensus decisions and adherence to advice following discussion at a weekly neurovascular multidisciplinary meeting.

BACKGROUND/AIMS: Data are limited on the frequency of 'consensus decisions' between sub-specialists attending a neurovascular multidisciplinary meeting (MDM) regarding management of patients with extracranial carotid/vertebral stenoses and post-MDM 'adherence' to such advice. METHODS: This prospective audit/quality improvement project collated prospectively-recorded data from a weekly Neurovascular/Stroke Centre MDM documenting the proportion of extracranial carotid/vertebral stenosis patients in whom 'consensus management decisions' were reached by neurologists, vascular surgeons, stroke physicians-geriatricians and neuroradiologists. Adherence to MDM advice was analysed in asymptomatic carotid stenosis (ACS), symptomatic carotid stenosis (SCS), 'indeterminate symptomatic status stenosis' (ISS) and vertebral artery stenosis (VAS) patients, including intervals between index event to MDM + / - intervention. RESULTS: One hundred fifteen patients were discussed: 108 with carotid stenosis and 7 with VAS. Consensus regarding management was noted in 96.5% (111/115): 100% with ACS and VAS, 96.2% with SCS and 92.9% with ISS. Adherence to MDM management advice was 96.4% (107/111): 100% in ACS, ISS and VAS patients; 92% (46/50) in SCS patients. The median interval from index symptoms to revascularisation in 50-99% SCS patients was 12.5 days (IQR: 9-18.3 days; N = 26), with a median interval from MDM to revascularisation of 5.5 days (IQR: 1-7 days). Thirty patients underwent revascularisation. Two out of twenty-nine patients (6.9%) with either SCS or ISS had a peri-procedural ipsilateral ischaemic stroke, with no further strokes/deaths during 3-months follow-up. CONCLUSIONS: The high frequency of inter-specialty consensus regarding management and adherence to proposed treatment supports a collaborative/multidisciplinary model of care in patients with extracranial arterial stenoses. Service development should aim to shorten times between MDM discussion-intervention and optimise prevention of stroke/death.

Enhanced ex vivo inhibition of platelet function following addition of dipyridamole to aspirin after transient ischaemic attack or ischaemic stroke: first results from the TRinity AntiPlatelet responsiveness (TrAP) study.

Ex vivo dipyridamole 'non-responsiveness' has not been extensively studied in ischaemic cerebrovascular disease. Platelet surface marker expression, leucocyte-platelet complex formation and inhibition of platelet function at high shear stress as detected by the PFA-100® Collagen-Adenosine-diphosphate (C-ADP) and Collagen-Epinephrine cartridges was assessed in 52 patients within 4 weeks of transient ischaemic attack (TIA) or ischaemic stroke on aspirin, and then 14 d (14 d) and >90 d (90 d) after adding dipyridamole. A novel definition of 'Dipyridamole non-responsiveness' was used. The median C-ADP closure time increased following addition of dipyridamole, remained elevated at 90 d (P ≤ 0·03), and was unaffected by aspirin dose. 59% at 14 d and 56% at 90 d were 'dipyridamole non-responders' on the PFA-100. The proportion of non-responders at 14 and 90 d was similar (P= 0·9). Compared with baseline (4·6%), median monocyte-platelet complexes increased at 14 d (5·0%, P= 0·03) and 90 d (4·9%, P= 0·04). Low C-ADP closure times were associated with increased monocyte-platelet complexes at 14 d (r= -0·32, P= 0·02) and 90 d (r= -0·33, P = 0·02). Monocyte-platelet complexes increased in the subgroup of dipyridamole non-responders on the PFA-100 (P≤ 0·045), but not in responders (P ≥ 0·5), at 14 and 90 d versus baseline. Additional inhibition of platelet function has been detected with the PFA-100 when dipyridamole is added to aspirin. Elevated monocyte-platelet complexes may contribute to ex vivo dipyridamole non-responsiveness.

Sequential fluctuating paraneoplastic ocular flutter-opsoclonus-myoclonus syndrome and Lambert-Eaton myasthenic syndrome in small-cell lung cancer.

Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously reported. A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar' signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus syndrome.

Progressive dysphagia in limb-girdle muscular dystrophy type 2B.

Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued. Endoscopic and videofluoroscopic-radiological findings indicated a myopathic swallowing disorder. Molecular genetic analysis confirmed two dysferlin gene mutations consistent with a compound heterozygote state. Progressive dysphagia should be considered as part of the expanding dysferlinopathy phenotype.

European Stroke Organisation guideline on endarterectomy and stenting for carotid artery stenosis.

Atherosclerotic stenosis of the internal carotid artery is an important cause of stroke. The aim of this guideline is to analyse the evidence pertaining to medical, surgical and endovascular treatment of patients with carotid stenosis. These guidelines were developed based on the ESO standard operating procedure and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote recommendations. Based on moderate quality evidence, we recommend carotid endarterectomy (CEA) in patients with ≥60-99% asymptomatic carotid stenosis considered to be at increased risk of stroke on best medical treatment (BMT) alone. We also recommend CEA for patients with ≥70-99% symptomatic stenosis, and we suggest CEA for patients with 50-69% symptomatic stenosis. Based on high quality evidence, we recommend CEA should be performed early, ideally within two weeks of the last retinal or cerebral ischaemic event in patients with ≥50-99% symptomatic stenosis. Based on low quality evidence, carotid artery stenting (CAS) may be considered in patients < 70 years old with symptomatic ≥50-99% carotid stenosis. Several randomised trials supporting these recommendations were started decades ago, and BMT, CEA and CAS have evolved since. The results of another large trial comparing outcomes after CAS versus CEA in patients with asymptomatic stenosis are anticipated in the near future. Further trials are needed to reassess the benefits of carotid revascularisation in combination with modern BMT in subgroups of patients with carotid stenosis.

European Stroke Organisation guideline on endarterectomy and stenting for carotid artery stenosis.

Atherosclerotic stenosis of the internal carotid artery is an important cause of stroke. The aim of this guideline is to analyse the evidence pertaining to medical, surgical and endovascular treatment of patients with carotid stenosis. These guidelines were developed based on the ESO standard operating procedure and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and wrote recommendations. Based on moderate quality evidence, we recommend carotid endarterectomy (CEA) in patients with ≥60-99% asymptomatic carotid stenosis considered to be at increased risk of stroke on best medical treatment (BMT) alone. We also recommend CEA for patients with ≥70-99% symptomatic stenosis, and we suggest CEA for patients with 50-69% symptomatic stenosis. Based on high quality evidence, we recommend CEA should be performed early, ideally within two weeks of the last retinal or cerebral ischaemic event in patients with ≥50-99% symptomatic stenosis. Based on low quality evidence, carotid artery stenting (CAS) may be considered in patients < 70 years old with symptomatic ≥50-99% carotid stenosis. Several randomised trials supporting these recommendations were started decades ago, and BMT, CEA and CAS have evolved since. The results of another large trial comparing outcomes after CAS versus CEA in patients with asymptomatic stenosis are anticipated in the near future. Further trials are needed to reassess the benefits of carotid revascularisation in combination with modern BMT in subgroups of patients with carotid stenosis.

Moyamoya disease and moyamoya syndrome in Ireland: patient demographics, mode of presentation and outcomes of EC-IC bypass surgery.

BACKGROUND: There are no previously published reports regarding the epidemiology and characteristics of moyamoya disease or syndrome in Ireland. AIMS: To examine patient demographics, mode of presentation and the outcomes of extracranial-intracranial bypass surgery in the treatment of moyamoya disease and syndrome in Ireland. METHODS: All patients with moyamoya disease and syndrome referred to the National Neurosurgical Centre during January 2012-January 2019 were identified through a prospective database. Demographics, clinical presentation, radiological findings, surgical procedures, postoperative complications and any strokes during follow-up were recorded. RESULTS: Twenty-one patients were identified. Sixteen underwent surgery. Median age at diagnosis was 19 years. Fifteen were female. Mode of presentation was ischaemic stroke in nine, haemodynamic TIAs in eight, haemorrhage in three and incidental in one. Sixteen patients had Moyamoya disease, whereas five patients had moyamoya syndrome. Surgery was performed on 19 hemispheres in 16 patients. The surgical procedures consisted of ten direct (STA-MCA) bypasses, five indirect bypasses and four multiple burr holes. Postoperative complications included ischaemic stroke in one patient and subdural haematoma in one patient. The median follow-up period in the surgical group was 52 months; there was one new stroke during this period. Two patients required further revascularisation following recurrent TIAs. One patient died during follow-up secondary to tumour progression associated with neurofibromatosis type 1. CONCLUSIONS: Moyamoya is rare but occurs in Caucasians in Ireland. It most commonly presents with ischaemic symptoms. Surgical intervention in the form of direct and indirect bypass is an effective treatment in the majority of cases.