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.

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.

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.

von Willebrand Factor Antigen, von Willebrand Factor Propeptide, and ADAMTS13 in Carotid Stenosis and Their Relationship with Cerebral Microemboli.

BACKGROUND: The relationship between von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio, ADAMTS13 activity, and microembolic signal (MES) status in carotid stenosis is unknown. METHODS: This prospective, multicenter study simultaneously assessed plasma VWF:Ag levels, VWFpp levels and ADAMTS13 activity, and their relationship with MES in asymptomatic versus symptomatic moderate-to-severe (≥50-99%) carotid stenosis patients. One-hour transcranial Doppler ultrasound of the middle cerebral arteries classified patients as MES+ve or MES-ve. RESULTS: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the "early phase" (≤4 weeks) and 37 patients in the "late phase" (≥3 months) after transient ischemic attack (TIA)/ischemic stroke. VWF:Ag levels were higher (p = 0.049) and VWFpp/VWF:Ag ratios lower (p = 0.006) in early symptomatic than in asymptomatic patients overall, and in early symptomatic versus asymptomatic MES-ve subgroups (p ≤0.02). There were no intergroup differences in VWFpp expression or ADAMTS13 activity (p ≥0.05). VWF:Ag levels and ADAMTS13 activity decreased (p ≤ 0.048) and VWFpp/VWF:Ag ratios increased (p = 0.03) in symptomatic patients followed up from the early to late phases after TIA/stroke. Although there were no differences in the proportions of symptomatic and asymptomatic patients with blood group O, a combined analysis of early symptomatic and asymptomatic patients revealed lower median VWF:Ag levels in patients with blood group O versus those without blood group O (9.59 vs. 12.32 µg/mL, p = 0.035). DISCUSSION: VWF:Ag expression, a marker of endothelial ± platelet activation, is enhanced in recently symptomatic versus asymptomatic carotid stenosis patients, including in MES-ve patients, and decreases with ADAMTS13 activity over time following atherosclerotic TIA/ischemic stroke.

Platelet function/reactivity testing and prediction of risk of recurrent vascular events and outcomes after TIA or ischaemic stroke: systematic review and meta-analysis.

BACKGROUND: The prevalence of ex vivo 'high on-treatment platelet reactivity (HTPR)' and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear. METHODS: A systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library were searched for completed manuscripts until May 2019 on TIA/ischaemic stroke patients, ≥ 18 years, treated with commonly-prescribed antiplatelet therapy, who had platelet function/reactivity testing and prospective follow-up data on recurrent stroke/TIA, myocardial infarction, vascular death or other cerebrovascular outcomes. Data were pooled using random-effects meta-analysis. Primary outcome was the composite risk of recurrent stroke/TIA, myocardial infarction or vascular death. Secondary outcomes were recurrent stroke/TIA, severe stroke (NIHSS > 16) or disability/impairment (modified Rankin scale ≥ 3) during follow-up. RESULTS: Antiplatelet-HTPR prevalence was 3-65% with aspirin, 8-56% with clopidogrel and 1.8-35% with aspirin-clopidogrel therapy. Twenty studies (4989 patients) were included in our meta-analysis. There was a higher risk of the composite primary outcome (OR 2.93, 95% CI 1.90-4.51) and recurrent ischaemic stroke/TIA (OR 2.43, 95% CI 1.51-3.91) in patients with vs. those without 'antiplatelet-HTPR' on any antiplatelet regimen. These risks were also more than twofold higher in patients with vs. those without 'aspirin-HTPR' and 'dual antiplatelet-HTPR', respectively. Clopidogrel-HTPR status did not significantly predict outcomes, but the number of eligible studies was small. The risk of severe stroke was higher in those with vs. without antiplatelet-HTPR (OR 2.65, 95% CI 1.00-7.01). DISCUSSION: Antiplatelet-HTPR may predict risks of recurrent vascular events/outcomes in CVD patients. Given the heterogeneity between studies, further prospective, multi-centre studies are warranted.

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.

Increased Leucocyte-Platelet Complex Formation in Recently Symptomatic versus Asymptomatic Carotid Stenosis Patients and in Micro-emboli Negative Subgroups.

INTRODUCTION: Cerebral micro-embolic signals (MES) predict risk of stroke in carotid stenosis patients. However, MES-negative 'recently symptomatic patients' also have a higher stroke risk than 'asymptomatic patients'. Differences in platelet activation status may contribute to this disparity in risk. METHODS: This prospective, observational study assessed platelet biomarkers and their relationship with MES in asymptomatic versus symptomatic moderate (≥50-69%) or severe (≥70-99%) carotid stenosis patients. Full blood count parameters were measured and whole-blood flow cytometry was used to quantify platelet surface CD62P and CD63 expression and leucocyte-platelet complex formation. Bilateral simultaneous transcranial Doppler ultrasound of the middle cerebral arteries classified patients as 'MES positive' or 'MES negative'. RESULTS: Data from 34 asymptomatic patients were compared with those from 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 of these symptomatic patients in the 'late phase' (≥ 3 months) after transient ischaemic attack/ischaemic stroke. There were no differences in %CD62P or %CD63 expression between early or late symptomatic and asymptomatic patients overall (p > 0.05). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic patients (2.8 vs. 2.16%; p < 0.001). MES were more commonly observed in early symptomatic (31.4%; p = 0.027) but not in late symptomatic (6.7%; p = 0.996) versus asymptomatic patients (7.1%). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic MES-negative patients (2.7 vs. 2.17%; p = 0.02). CONCLUSION: These data add to the evidence that leucocyte-platelet complex formation/platelet activation is increased in recently symptomatic versus asymptomatic patients, and may contribute to the pathogenesis of first and subsequent strokes in carotid stenosis patients, including those who are MES negative.

The experience of recurrent fallers in the first year after stroke.

PURPOSE: Understanding the experiences of fallers after stroke could inform falls-prevention interventions, which have not yet shown effectiveness in this population. The aim of this study was to explore the experience of recurrent fallers post-stroke in relation to recovery and living with falls. METHODS: Participants who had more than one fall in the first year after stroke were identified from a prospective cohort study. The methods of grounded theory informed data collection and analysis. Semi-structured interviews were conducted, audio-recorded and transcribed. Coding was conducted and categories were developed inductively. RESULTS: Nine stroke survivors aged 53-85 were interviewed 18-22 months post-discharge. Participants had experienced between 2 and 9 falls and one participant suffered a fracture. Three inter-linked categories were identified: (i) Judging the importance of falls by exploring cause and consequence, (ii) getting back up, and (iii) being careful. CONCLUSIONS: Stroke survivors' assessment of their own falls-risk and their individual priorities contribute to their decisions around activity participation. "Being careful" could be described as a form of self-managing falls-risk. The inclusion of self-management principles, peer-educators, and education to rise from the floor in falls-management programmes warrants investigation. Not all falls were considered equally important by participants. This could be considered when defining falls-related outcomes. Implications for Rehabilitation Healthcare professionals may be able to offer an increased sense of control to stroke survivors through education about how to avoid particular causes and consequences of falls. Falls-related advice should be specific, relevant to the individual, and respectful of their sense of identity. Being able to rise from the floor appears to be important for coping with falls and falls-risk. Professionals should be cognisant of the potential differences of opinion between stroke survivors and their families around management of falls-risk.

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.

Restenosis and risk of stroke after stenting or endarterectomy for symptomatic carotid stenosis in the International Carotid Stenting Study (ICSS): secondary analysis of a randomised trial.

BACKGROUND: The risk of stroke associated with carotid artery restenosis after stenting or endarterectomy is unclear. We aimed to compare the long-term risk of restenosis after these treatments and to investigate if restenosis causes stroke in a secondary analysis of the International Carotid Stenting Study (ICSS). METHODS: ICSS is a parallel-group randomised trial at 50 tertiary care centres in Europe, Australia, New Zealand, and Canada. Patients aged 40 years or older with symptomatic carotid stenosis measuring 50% or more were randomly assigned either stenting or endarterectomy in a 1:1 ratio. Randomisation was computer-generated and done centrally, with allocation by telephone or fax, stratified by centre, and with minimisation for sex, age, side of stenosis, and occlusion of the contralateral carotid artery. Patients were followed up both clinically and with carotid duplex ultrasound at baseline, 30 days after treatment, 6 months after randomisation, then annually for up to 10 years. We included patients whose assigned treatment was completed and who had at least one ultrasound examination after treatment. Restenosis was defined as any narrowing of the treated artery measuring 50% or more (at least moderate) or 70% or more (severe), or occlusion of the artery. The degree of restenosis based on ultrasound velocities and clinical outcome events were adjudicated centrally; assessors were masked to treatment assignment. Restenosis was analysed using interval-censored models and its association with later ipsilateral stroke using Cox regression. This trial is registered with the ISRCTN registry, number ISRCTN25337470. This report presents a secondary analysis, and follow-up is complete. FINDINGS: Between May, 2001, and October, 2008, 1713 patients were enrolled and randomly allocated treatment (855 were assigned stenting and 858 endarterectomy), of whom 1530 individuals were followed up with ultrasound (737 assigned stenting and 793 endarterectomy) for a median of 4·0 years (IQR 2·3-5·0). At least moderate restenosis (≥50%) occurred in 274 patients after stenting (cumulative 5-year risk 40·7%) and in 217 after endarterectomy (29·6%; unadjusted hazard ratio [HR] 1·43, 95% CI 1·21-1·72; p<0·0001). Patients with at least moderate restenosis (≥50%) had a higher risk of ipsilateral stroke than did individuals without restenosis in the overall patient population (HR 3·18, 95% CI 1·52-6·67; p=0·002) and in the endarterectomy group alone (5·75, 1·80-18·33; p=0·003), but no significant increase in stroke risk after restenosis was recorded in the stenting group (2·03, 0·77-5·37; p=0·154; p=0·10 for interaction with treatment). No difference was noted in the risk of severe restenosis (≥70%) or subsequent stroke between the two treatment groups. INTERPRETATION: At least moderate (≥50%) restenosis occurred more frequently after stenting than after endarterectomy and increased the risk for ipsilateral stroke in the overall population. Whether the restenosis-mediated risk of stroke differs between stenting and endarterectomy requires further research. FUNDING: Medical Research Council, the Stroke Association, Sanofi-Synthélabo, and the European Union.

Increased platelet count and reticulated platelets in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic signal-negative patient subgroups: results from the HaEmostasis In carotid STenosis (HEIST) study.

BACKGROUND: The pathophysiological mechanisms responsible for the disparity in stroke risk between asymptomatic and symptomatic carotid stenosis patients are not fully understood. The functionally important reticulated platelet fraction and reticulocytes could play a role. OBJECTIVES: We performed a prospective, multi-centre, observational analytical study comparing full blood count parameters and platelet production/turnover/activation markers in patients with asymptomatic versus recently symptomatic moderate (≥ 50-69%) or severe (≥ 70-99%) carotid stenosis. PATIENTS/METHODS: Data from 34 asymptomatic patients were compared with 43 symptomatic patients in the 'early phase' (≤ 4 weeks) and 37 of these patients in the 'late phase' (≥ 3 months) after TIA/ischaemic stroke. Reticulated platelets were quantified by whole blood flow cytometry and reticulated platelets and red cell reticulocytes by 'automated assays' (Sysmex XE-2100™). Bilateral simultaneous transcranial Doppler ultrasound monitoring classified patients as micro-embolic signal (MES)+ve or MES-ve. RESULTS: Mean platelet count was higher in early (216 × 109/L; P = 0.04) and late symptomatic (219 × 109/L; P = 0.044) than asymptomatic patients (194 × 109/L). Mean platelet volume was higher in early symptomatic than asymptomatic patients (10.8 vs. 10.45 fl; P = 0.045). Automated assays revealed higher % reticulated platelet fractions in early (5.78%; P < 0.001) and late symptomatic (5.11%; P = 0.01) than asymptomatic patients (3.48%). Red cell reticulocyte counts were lower in early (0.92%; P = 0.035) and late symptomatic (0.93%; P = 0.036) than asymptomatic patients (1.07%). The automated % reticulated platelet fraction was also higher in early symptomatic than asymptomatic MES-ve patients (5.7 vs. 3.55%; P = 0.001). DISCUSSION: The combination of increased platelet counts and a shift towards production of an increased population of larger, young, reticulated platelets could contribute to a higher risk of first or recurrent cerebrovascular events in recently symptomatic versus asymptomatic carotid stenosis, including those who are MES-ve.

Aciclovir-induced acute kidney injury in patients with 'suspected viral encephalitis' encountered on a liaison neurology service.

BACKGROUND: Patients with 'suspected viral encephalitis' are frequently empirically treated with intravenous aciclovir. Increasing urea and creatinine are 'common', but rapidly progressive renal failure is reported to be 'very rare'. AIMS: To describe the clinical course and outcome of cases of aciclovir-induced acute kidney injury (AKI) encountered by the Liaison Neurology Service at AMNCH and to highlight the importance of surveillance and urgent treatment of this iatrogenic complication. METHODS: Retrospectively and prospectively collected data from the Liaison Neurology Service at AMNCH on patients who received IV aciclovir for suspected viral encephalitis and developed AKI were analysed. Aciclovir-induced AKI was defined by a consultant nephrologist in all cases as a rise in serum creatinine of > 26 µmol/L in 48 h or by ≥ 1.5 times the baseline value. Renal function, haematocrit, and fluid balance were monitored following AKI onset. RESULTS: Data from 10 patients were analysed. Median time to AKI onset was 3.5 days (range: 1-6 days). Aciclovir was stopped or the dose adjusted. All patients recovered with IV normal saline, aiming for a urine output > 100-150 ml/h. The interval between first rise in creatinine and return to normal levels varied between 5 and 19 days. CONCLUSIONS: Liaison neurologists and general physicians need to be aware that aciclovir may cause AKI attributed to distal intra-tubular crystal nephropathy. Daily fluid balance and renal function monitoring are essential because AKI may arise even with intensive pre-hydration. Prognosis is good if identified early and actively treated.

Extracranial and Intracranial Vasculopathy With "Moyamoya Phenomenon" in Association With Alagille Syndrome.

Background: Alagille syndrome (AGS) is an autosomal-dominant, multisystem disorder caused by mutations in the JAG1 gene. Case Description: A 34-year-old man was referred to our service 10 years ago with focal seizures with impaired awareness and transient slurred speech. He had a 5-year history of intermittent left monocular low-flow retinopathy. He has a family history of AGS. General examination revealed mild hypertension, aortic regurgitation, and livedo reticularis. Neurological examination was normal. Investigations: He had mild hyperlipidaemia and persistently-positive lupus anticoagulant consistent with primary anti-phospholipid syndrome. Color Doppler ultrasound revealed low velocity flow in a narrowed extracranial left internal carotid artery (ICA). MR and CT angiography revealed a diffusely narrowed extracranial and intracranial left ICA. Formal cerebral angiography confirmed severe left ICA narrowing consistent with a left ICA "vasculopathy" and moyamoya phenomenon. Transthoracic echocardiogram revealed a bicuspid aortic valve and aortic incompetence. Molecular genetic analysis identified a missense mutation (A211P) in exon 4 of the JAG1 gene, consistent with AGS. Discussion: AGS should be considered in young adults with TIAs/stroke and unexplained extracranial or intracranial vascular abnormalities, and/or moyamoya phenomenon, even in the absence of other typical phenotypic features. Gene panels should include JAG1 gene testing in similar patients.

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.

Clinical outcomes and a high prevalence of abnormalities on comprehensive arterial and venous thrombophilia screening in TIA or ischaemic stroke patients with a patent foramen ovale, an inter-atrial septal aneurysm or both.

INTRODUCTION: Data are limited on the optimal management of cryptogenic TIA/stroke patients with a patent foramen ovale (PFO)±inter-atrial septal aneurysm (IASA), especially with an inherited thrombophilia. METHODS: Prospectively-collected data on TIA/ischaemic stroke patients with PFO, IASA or both who received 'goal-directed secondary-prevention medical treatment' were analysed. All patients had trans-oesophageal echocardiography, anti-nuclear, anti-cardiolipin, anti-beta 2 glycoprotein I antibodies, rheumatoid factor, lupus anticoagulant, protein C&S, anti-thrombin, factor VIII activity, activated protein C resistance, Factor V Leiden, prothrombin gene and MTHFR-c.677C>T mutation screening. ENA and homocysteine were assessed in the latter study period. RESULTS: Eighty-three patients were recruited. Mean follow-up: 48.1months. Forty-seven patients (56.6%) had an isolated PFO, 32 (38.6%) a PFO and an IASA, and 4 (4.8%) an IASA alone. Eighteen (21.7%) had ≥1 abnormality on thrombophilia screening. The most important abnormalities which lead to treatment changes in 11 patients (13.3%) were primary anti-phospholipid syndrome (N=3; 3.6%), protein S deficiency (N=2; 2.4%) hyper-homocysteinaemia (N=6/72 screened, 8.3%). Four patients (4.8%) opted for PFO closure: two with protein S deficiency, and two with no identified thrombophilia. Seven (8.4%) had recurrent TIA/ischaemic stroke during follow-up (overall annualised incidence: 2.1%), of whom five had a PFO alone and two a PFO and IASA. DISCUSSION: Comprehensive arterial and venous thrombophilia screening is warranted in TIA/ischaemic stroke patients with a PFO±IASA, is conclusively abnormal in over a fifth, and informed important decision-making regarding individualised therapy in 13.3% of patients. The incidence of recurrent vascular events in this population is low on optimal, personalised secondary-prevention treatment, even with an underlying thrombophilia.

Assessment of 'on-treatment platelet reactivity' and relationship with cerebral micro-embolic signals in asymptomatic and symptomatic carotid stenosis.

INTRODUCTION: The relationship between on-treatment platelet reactivity and cerebral micro-embolic signals (MES) is unknown, and has not been previously simultaneously assessed in asymptomatic and symptomatic carotid stenosis patients. METHODS: Consecutive eligible patients with ≥50% asymptomatic or recently symptomatic carotid stenosis (≤4weeks following TIA/ischaemic stroke) were recruited to this pilot study. Symptomatic patients were followed up to the 'late' phase (≥3months) following symptom onset or carotid intervention; longitudinal data were analysed from symptomatic patients with data available at both time-points. Platelet function/reactivity was assessed with the PFA-100® to measure collagen-ADP (C-ADP) and collagen-epinephrine (C-EPI) closure times in citrate-anticoagulated whole blood. Bilateral simultaneous 1-hour transcranial Doppler ultrasound (TCD) monitoring of the middle cerebral arteries was performed to classify patients as MES +ve or MES -ve. RESULTS: 31 patients with ≥50% asymptomatic and 46 with early symptomatic carotid stenosis or occlusion were included. 35 symptomatic patients were followed up to the late phase (23 following carotid intervention). Prevalence of 'high on-treatment platelet reactivity' (HTPR) on the C-EPI cartridge did not differ between asymptomatic and symptomatic patients overall, but was lower in 'symptomatic post-intervention' than asymptomatic patients on aspirin monotherapy (10% vs. 50%; p=0.03). The prevalence of HTPR on the C-EPI cartridge decreased between the early and late phases in symptomatic patients (63% vs. 34%; p=0.017), including those on aspirin monotherapy (p=0.016). There were no significant differences in HTPR status between asymptomatic vs. early or late symptomatic MES +ve or MES -ve patients. DISCUSSION: Carotid interventional treatment, presumably in combination with resolution of the acute phase response, may decrease the prevalence of HTPR in patients with recently symptomatic carotid stenosis over time. Preliminary subgroup analysis suggests that successful intervention may reduce the prevalence of aspirin-HTPR in symptomatic patients to lower levels than asymptomatic medically-treated patients on aspirin monotherapy. Larger, longitudinal studies are warranted to reassess the impact of more intensive secondary preventive treatment on ex vivo platelet function at different levels of shear stress in carotid stenosis patients.