von Willebrand factor antigen, von Willebrand factor propeptide and ADAMTS13 activity in TIA or ischaemic stroke patients changing antiplatelet therapy.

Data are limited on the impact of commencing antiplatelet therapy on von Willebrand Factor Antigen (VWF:Ag) or von Willebrand Factor propeptide (VWFpp) levels and ADAMTS13 activity, and their relationship with platelet reactivity following TIA/ischaemic stroke. In this pilot, observational study, VWF:Ag and VWFpp levels and ADAMTS13 activity were quantified in 48 patients ≤4 weeks of TIA/ischaemic stroke (baseline), and 14 days (14d) and 90 days (90d) after commencing aspirin, clopidogrel or aspirin+dipyridamole. Platelet reactivity was assessed at moderately-high shear stress (PFA-100® Collagen-Epinephrine / Collagen-ADP / INNOVANCE PFA P2Y assays), and low shear stress (VerifyNow® Aspirin / P2Y12, and Multiplate® Aspirin / ADP assays). VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d in the overall population (P ≤ 0.03). In the clopidogrel subgroup, VWF:Ag levels decreased and VWFpp/VWF:Ag ratio increased between baseline and 14d and 90d (P ≤ 0.01), with an increase in ADAMTS13 activity between baseline vs. 90d (P ≤ 0.03). In the aspirin+dipyridamole subgroup, there was an inverse relationship between VWF:Ag and VWFpp levels with both PFA-100 C-ADP and INNOVANCE PFA P2Y closure times (CTs) at baseline (P ≤ 0.02), with PFA-100 C-ADP, INNOVANCE PFA P2Y and C-EPI CTs at 14d (P ≤ 0.05), and between VWF:Ag levels and PFA-100 INNOVANCE PFA P2Y CTs at 90d (P = 0.03). There was a positive relationship between ADAMTS13 activity and PFA-100 C-ADP CTs at baseline (R2 = 0.254; P = 0.04). Commencing/altering antiplatelet therapy, mainly attributed to commencing clopidogrel in this study, was associated with decreasing endothelial activation following TIA/ischaemic stroke. These data enhance our understanding of the impact of VWF:Ag and VWFpp especially on ex-vivo platelet reactivity status at high shear stress after TIA/ischaemic stroke.

Assessment of on-treatment platelet reactivity at high and low shear stress and platelet activation status after the addition of dipyridamole to aspirin in the early and late phases after TIA and ischaemic stroke.

BACKGROUND: Data are limited on the ability of dipyridamole to additionally inhibit platelet function/reactivity in ischaemic cerebrovascular disease (CVD) patients on aspirin. AIMS: To assess inhibition of platelet function/reactivity and platelet activation with dipyridamole in CVD. METHODS: This prospective, observational study assessed TIA/ischaemic stroke patients before (baseline; N = 60), at 14 ±7 days (14d, N = 39) and ≥ 90 days (90d, N = 31) after adding dipyridamole to aspirin. Platelet function/reactivity at high shear stress (PFA-100® C-ADP) and low shear stress (VerifyNow® P2Y12 and Multiplate® ADP assays), and platelet activation status (% expression of CD62P, CD63 and leucocyte-platelet complexes on whole blood flow cytometry) were quantified. 'Dipyridamole-high on-treatment platelet reactivity (HTPR)' was defined as failure to inhibit ADP-induced platelet aggregation +/- adhesion compared with the patient's baseline on aspirin monotherapy by more than twice the coefficient-of-variation of the assay after adding dipyridamole to aspirin. RESULTS: Dipyridamole-HTPR was identified in 71.4-75% of patients on PFA-100 C-ADP, 83.9-86.8% of patients on VerifyNow P2Y12, and 81.5-83.3% of patients on Multiplate ADP assays. There were no changes in CD62P/CD63 expression (P ≥ 0.18), or consistent changes in leucocyte-platelet complexes in CVD patients overall at 14d or 90d vs. baseline after commencing dipyridamole. Monocyte-platelet complexes increased in the patient subgroup with dipyridamole-HTPR at 14d and 90d on PFA-100, and at 14d on VerifyNow (P ≤ 0.04), but not in those without dipyridamole-HTPR. DISCUSSION: Additional antiplatelet effects of dipyridamole are detectable under high and low shear stress conditions with user-friendly platelet function/reactivity tests ex vivo. Increasing circulating monocyte-platelet complexes over time are associated with dipyridamole-HTPR.

Assessment of the adequacy of counselling regarding reproductive-related issues in women of childbearing age on anti-epileptic drugs.

BACKGROUND: The use of anti-epileptic drugs (AEDs) in women of childbearing age (WCBA) necessitates careful counselling regarding reproductive-related issues. AIM: (i) To compare documentation of appropriate counselling regarding reproductive-related issues in WCBA prescribed AEDs for non-epilepsy vs. epilepsy indications, and (ii) to examine whether the frequency of counselling improved after introduction of 'standardized typed advice'. DESIGN: Retrospective audit and quality assessment and improvement programme. METHODS: We analysed medical records of all WCBA prescribed gabapentin, pregabalin, topiramate, valproate or carbamazepine by a general neurology clinical service before (Study period A) and after (Study period B) introduction of standardized typed passages regarding potential teratogenicity ± interactions with hormonal contraception at a university teaching hospital. The χ2 test or the Fisher's exact test was employed, as appropriate. RESULTS: In WCBA prescribed AEDs for non-epilepsy indications, documentation of appropriate counselling regarding potential teratogenicity improved from 49% (17/35 patients) in Period A to 79% (27/34 patients) in Period B (P = 0.008). The frequency of counselling regarding teratogenicity was higher in patients prescribed AEDs for epilepsy compared with non-epilepsy indications in Study period A (100% vs. 49%, P = 0.002), but was no longer significantly different in Study period B (86% vs. 79%, P = 0.64). Documentation of counselling regarding potential interaction of enzyme-inducing AEDs with hormonal contraception did not significantly change between study periods. CONCLUSION: Significant improvements in documentation regarding potential teratogenicity of AEDs prescribed for non-epilepsy indications can be achieved by introducing standardized, typed passages copied to patients. Such a practice change is practical and widely applicable to neurological and non-neurological practice worldwide.

Relationship between 'on-treatment platelet reactivity', shear stress, and micro-embolic signals in asymptomatic and symptomatic carotid stenosis.

BACKGROUND: Assessment of 'high on-treatment platelet reactivity (HTPR)' could enhance understanding of the pathophysiology of first or recurrent vascular events in carotid stenosis patients on antiplatelet therapy. METHODS: This prospective, multi-centre study assessed antiplatelet-HTPR status and its relationship with micro-emboli signals (MES) in asymptomatic vs. symptomatic ≥ 50-99% carotid stenosis. Platelet function/reactivity was assessed under 'moderately high shear stress' with the PFA-100® and 'low shear stress' with VerifyNow® and Multiplate® analysers. Bilateral 1-h 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 TIA/ischaemic stroke. Median daily aspirin doses were higher in early symptomatic (225 mg; P < 0.001), but not late symptomatic (75 mg; P = 0.62) vs. asymptomatic patients (75 mg). There was a lower prevalence of aspirin-HTPR in early (28.6%; P = 0.028), but not late symptomatic (38.9%; P = 0.22) compared with asymptomatic patients (56.7%) on the PFA-100®, but not on the VerifyNow® or Multiplate® (P ≤ 0.53). Early symptomatic patients had a higher prevalence of aspirin-HTPR on the PFA-100® (28.6%) vs. VerifyNow® (9.5%; P = 0.049), but not Multiplate® assays (11.9%, P = 0.10). There was no difference in aspirin-HTPR prevalence between any symptomatic vs. asymptomatic MES + ve or MES - ve subgroup. DISCUSSION: Recently symptomatic moderate-severe carotid stenosis patients had a lower prevalence of aspirin-HTPR than their asymptomatic counterparts on the PFA-100®, likely related to higher aspirin doses. The prevalence of antiplatelet-HTPR was positively influenced by higher shear stress levels, but not MES status.

Patterns of mortality in modern stroke care

Background Stroke is a leading cause of death. We looked at the causes (direct and indirect) of in-hospital mortality in a modern stroke unit over a two-year period. Methods We reviewed medical charts of stroke deaths in hospital from 2014-2015 inclusive. Data on stroke type, aetiology, age, length of stay, comorbidities, and documented cause of death were recorded. All patients were included. Results 518 patients were admitted acutely to the stroke service. Overall death rate was 7.5% (n=39). Of fatal strokes 29 (74%) were ischaemic. Average age 78.6 years. Mean survival was 26.4 days (range 1-154). 19 (49%) patients had atrial fibrillation. Forty-nine percent of deaths were due to pneumonia, and 33% were due to raised intracranial pressure. Discussion Mortality rate in our stroke service has decreased from 15% in 1997, and now appears dichotomised into early Secondary Stroke Related Cerebral Events (SSRCEs) and later infections.

Carotid arteritis causing amaurosis fugax and ischaemic cerebrovascular events in neurosarcoidosis.

OBJECTIVE: To present and review the vascular consequences of arteritis in neurosarcoidosis. PATIENT AND METHODS: neurosarcoidosis is typically an inflammatory disorder of the meninges surrounding the brain and spinal cord. Although inflammation of small and medium sized vessels is seen pathologically and vasculitis is occasionally described, a large intracerebral arteritis has not previously been reported. A few case reports exist, however, which describe the vascular consequences of large vessel compromise in the disorder. We review the literature and present a new case with novel MRI features which imply carotid arteritis. RESULTS: The case presented with a disorder of the carotid artery on one side leading to a series of TIAs. Inflammation of the wall of the carotid artery was seen adjacent to a granulomatous leptomeningitis. The disorder responded to immunosuppressive therapy without recurrence. CONCLUSIONS: The imaging features suggest a granulomatous infiltration of the carotid artery wall leading to arteritis followed by disorganisation of the internal elastic lamina and fibrosis. The data provide further insight into the pathogenesis of neurological impairments in neurosarcoidosis. The MRI features of carotid arteritis in neurosarcoidosis have not previously been demonstrated.

Thrombolysis for stroke in Ireland: increasing access and maintaining safety in a challenging environment.

BACKGROUND: In the setting of a national audit of acute stroke services, we examined the delivery of thrombolytic therapy for ischaemic stroke and whether current practice was achieving safe outcomes and consistent delivery for patients. METHOD: Data obtained from the recent national stroke audit was compared against previous Irish audit, the most recent SSNAP UK stroke audit and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) study. RESULTS: Thrombolysis was provided in 27 acute hospitals throughout Ireland during the period assessed with 82% (22/27) providing 24/7 access, the remaining sites using redirect policies. Decision to thrombolyse was made by stroke trained consultants in 63% (17/27) of units, with general physicians and emergency medicine consultants covering the other units. Thrombolysis rate for non-haemorrhagic stroke was 11% (n = 80/742, CI 95% ±2.23) versus a 1% rate in the 2008 audit. Sites receiving patients through a redirect policy had the highest thrombolysis rate, an average of 24%. Nearly 30% of cases were thrombolysed on the weekend. Eighty-three percent of cases were managed in a stroke unit at some time during admission versus 54% of the national total cases. Thirty-seven percent of patients were ≥80 years old. The mortality rate was 11.3% versus the national mortality rate for non-thrombolysed ischaemic strokes of 10% (p > 0.5), and this is comparable to the SITS-MOST 2007 study 3-month mortality rate of 11.3% (p > 0.5). CONCLUSION: Stroke thrombolysis is being effectively and safely provided in acute stroke services in Ireland despite regular involvement of non-specialist staff. There is still potential to improve thrombolysis rate.

Dissociated Agonist of Glucocorticoid Receptor or Prednisone for Active Rheumatoid Arthritis: Effects on P1NP and Osteocalcin Pharmacodynamics.

Fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti-inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment-related changes in amino-terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed-effects longitudinal kinetic-pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were -18, -22, and -22% (P1NP), and -7, -13, and -17% (OC), respectively. Changes with prednisone 5 and 10 mg were -15% and -18% (P1NP) and -10% and -17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%.

Neurosarcoidosis: clinical presentations and changing treatment patterns in an Irish Caucasian population.

BACKGROUND: The clinical manifestations of neurosarcoidosis are highly variable and it should be considered as a potential differential diagnosis in any neurological presentation. AIM: This study was designed to describe the clinical, diagnostic, and treatment patterns and functional outcome in a Caucasian neurosarcoidosis population. DESIGN: A retrospective analysis was performed on prospectively recorded data in patients attending our neurology clinic between 2008 and 2014 with a diagnosis of definite or probable neurosarcoidosis according to Zajiek criteria. METHODS: Detailed clinical features, baseline demographic data, results of investigations, treatment type and duration, and clinical outcomes were collated. RESULTS: Eleven patients were identified (55% men) with mean age 39 years (range 21-63). Four had a prior history of systemic sarcoidosis leading to earlier diagnosis (6.7 vs 13.1 months). Six were found to have evidence of systemic sarcoidosis on further investigation and one was biopsy proven isolated neurosarcoidosis. The commonest site of CNS involvement was the cranial nerves (64%), and headache (45%) was the most frequent presenting symptom. MRI abnormalities included leptomeningeal enhancement, white matter lesions, acute arteritis, spinal cord lesion, and cauda equina enhancement. The commonest CSF finding was raised protein (n = 6) and a lymphocytic pleocytosis (n = 7). Serum ACE was only elevated in three cases. Ten patients were treated with both corticosteroids and steroid-sparing agents 8 of whom went into remission. CONCLUSIONS: This series highlights the diverse nature of neurosarcoidosis. Early introduction of aggressive therapy with corticosteroids and steroid-sparing agents appears to improve clinical outcome.

The impact of healthcare rationing on elective and emergency hernia repair.

PURPOSE: In 2011 the local clinical commissioning group introduced a policy restricting funding for elective hernia repairs. Anecdotally, it was felt that this resulted in an increased number of emergency hernia repairs in our trust. Our primary objective was to assess whether this was actually the case. Our secondary objective was to quantify the risks of non-elective hernia repair. METHODS: We performed a retrospective cohort study, analysing all hernia surgeries performed between 2010 and 2013. The data were obtained from the trust Patient Information System. A total of 2556 patients underwent repair of inguinal, umbilical, incisional, femoral or ventral hernias over this time. RESULTS: As the policy intended, the number of elective hernia repairs reduced from 857 over 12 months before the funding restrictions to 606 in the same period afterwards (p < 0.001). Over the same time period, however, a significant rise in total emergency hernia repairs was demonstrated, increasing from 98 to 150 (p < 0.001). 30-day readmission rates also increased from 5.1 % before the policy introduction to 8.5 % afterwards (p = 0.006). In our data, the rate of bowel resection rises from 0.97 to 12.9 % for emergency operation compared to elective hernia repair (p < 0.001), while the median length of stay rises from less than 24 h to 3 days. CONCLUSIONS: Our data suggest that the funding restrictions introduced in 2011 were followed by a statistically significant and unintended increase in emergency hernia repairs in our trust, with associated increased risks to patient safety.

Increased thrombin generation potential in symptomatic versus asymptomatic moderate or severe carotid stenosis and relationship with cerebral microemboli.

INTRODUCTION: The importance of thrombin generation in the pathogenesis of TIA or stroke and its relationship with cerebral microembolic signals (MES) in asymptomatic and symptomatic carotid stenosis has not been comprehensively assessed. METHODS: Plasma thrombin generation parameters from patients with moderate or severe (≥ 50%) asymptomatic carotid stenosis were compared with those from patients with symptomatic carotid stenosis in the early (≤ 4 weeks) and late phases (≥ 3 months) after TIA or stroke in this prospective, pilot observational study. Thrombin generation profile was longitudinally assessed in symptomatic patients with data at each time point. Bilateral transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed whenever possible to classify patients as MES-positive or MES-negative. RESULTS: Data from 31 asymptomatic, 46 'early symptomatic' and 35 'late symptomatic' patients were analysed. Peak thrombin (344.2 nM vs 305.3 nM; p = 0.01) and endogenous thrombin potential (1772.4 vs 1589.7; p = 0.047) were higher in early symptomatic than asymptomatic patients. Peak thrombin production decreased in symptomatic patients followed up from the early to late phase after TIA or stroke (339.7 nM vs 308.6 nM; p = 0.02). Transcranial Doppler ultrasound data were available in 25 asymptomatic, 31 early symptomatic and 27 late symptomatic patients. Early symptomatic MES-positive patients had a shorter 'time-to-peak thrombin' than asymptomatic MES-positive patients (p=0.04), suggesting a more procoagulant state in this early symptomatic subgroup. DISCUSSION: Thrombin generation potential is greater in patients with recently symptomatic than asymptomatic carotid stenosis, and decreases over time following TIA or stroke associated with carotid stenosis. These data improve our understanding of the haemostatic/thrombotic biomarker profile in moderate-severe carotid stenosis.

Longitudinal assessment of von Willebrand factor antigen and von Willebrand factor propeptide in response to alteration of antiplatelet therapy after TIA or ischaemic stroke.

The impact of commencing or changing antiplatelet therapy on von Willebrand factor antigen (VWF:Ag) and von Willebrand factor propeptide (VWF:Ag II) levels has not been comprehensively assessed following TIA or ischaemic stroke. In this pilot, longitudinal, observational analytical study, VWF:Ag and VWF:Ag II levels were simultaneously quantified in platelet poor plasma by ELISA in patients within 4 weeks of TIA or ischaemic stroke (baseline), and then 14 days (14d) and >90 days (90d) after altering antiplatelet therapy. Ninety-one patients were recruited. Eighteen were initially assessed on no antiplatelet therapy, and then after 14d (N = 17) and 90d (N = 8) on aspirin monotherapy; 21 patients were assessed on aspirin and after 14d and 90d on clopidogrel; 52 were assessed on aspirin monotherapy, and after 14d and 90d on aspirin and dipyridamole combination therapy. VWF:Ag, VWF:Ag II levels and VWF:Ag/VWF:Ag II ratio were unchanged at 14d and 90d in the overall study population (p ≥ 0.1). VWF:Ag and VWF:Ag II levels remained stable at 14d and 90d after commencing aspirin (p ≥ 0.054), and after changing from aspirin to clopidogrel (p ≥ 0.2). Following the addition of dipyridamole MR to aspirin, there was a significant reduction in VWF:Ag levels at 14d (p = 0.03) and 90d (p = 0.005), but not in VWF:Ag II levels (p ≥ 0.3). The addition of dipyridamole to aspirin led to a persistent reduction in VWF:Ag but not in VWF:Ag II levels, suggesting that dipyridamole may inhibit release of platelet-derived VWF:Ag following TIA or ischaemic stroke.

Increased endothelial activation in recently symptomatic versus asymptomatic carotid artery stenosis and in cerebral microembolic-signal-negative patient subgroups.

BACKGROUND AND PURPOSE: von Willebrand factor propeptide (VWF:Ag II) is potentially a more sensitive marker of acute endothelial activation than von Willebrand factor antigen (VWF:Ag). These biomarkers have not been simultaneously assessed in asymptomatic versus symptomatic carotid stenosis patients. The relationship between endothelial activation and cerebral microembolic signals (MESs) detected on transcranial Doppler ultrasound is unknown. METHODS: In this multicentre observational analytical study, plasma VWF:Ag and VWF:Ag II levels in patients with ≥50% asymptomatic carotid stenosis were compared with those from patients with ≥50% symptomatic carotid stenosis in the 'early' (≤4 weeks) and 'late' (≥3 months) phases after transient ischaemic attack or ischaemic stroke. Endothelial activation was also longitudinally assessed in symptomatic patients during follow-up. Transcranial Doppler ultrasound monitoring classified patients as MES-positive or MES-negative. RESULTS: Data from 31 asymptomatic patients were compared with those from 46 early symptomatic and 35 late phase symptomatic carotid stenosis patients, 23 of whom had undergone carotid intervention. VWF:Ag II levels were higher in early (12.8 µg/ml; P < 0.001), late (10.6 µg/ml; P = 0.01) and late post-intervention (10.6 µg/ml; P = 0.038) symptomatic patients than asymptomatic patients (8.9 µg/ml). VWF:Ag levels decreased in symptomatic patients followed up from the early to late phase after symptom onset (P = 0.048). Early symptomatic MES-negative patients had higher VWF: Ag II levels (13.3 vs. 9.0 µg/ml; P < 0.001) than asymptomatic MES-negative patients. CONCLUSIONS: Endothelial activation is enhanced in symptomatic versus asymptomatic carotid stenosis patients, in early symptomatic versus asymptomatic MES-negative patients, and decreases over time in symptomatic patients. VWF:Ag II levels are a more sensitive marker of endothelial activation than VWF:Ag levels in carotid stenosis. The potential value of endothelial biomarkers and concurrent cerebral MES detection at predicting stroke risk in carotid stenosis warrants further study.

Increased platelet activation in early symptomatic vs. asymptomatic carotid stenosis and relationship with microembolic status: results from the Platelets and Carotid Stenosis Study.

BACKGROUND: Cerebral microembolic signals (MES) may predict increased stroke risk in carotid stenosis. However, the relationship between platelet counts or platelet activation status and MES in symptomatic vs. asymptomatic carotid stenosis has not been comprehensively assessed. SETTING: University teaching hospitals. METHODS: This prospective, pilot observational study assessed platelet counts and platelet activation status, and the relationship between platelet activation and MES in asymptomatic vs. early (≤ 4 weeks after TIA/stroke) and late phase (≥ 3 months) symptomatic moderate or severe (≥ 50%) carotid stenosis patients. Full blood count measurements were performed, and whole blood flow cytometry was used to quantify platelet surface activation marker expression (CD62P and CD63) and circulating leucocyte-platelet complexes. Bilateral simultaneous transcranial Doppler ultrasound monitoring of the middle cerebral arteries was performed for 1 h to classify patients as MES positive or MES negative. RESULTS: Data from 31 asymptomatic patients were compared with 46 symptomatic patients in the early phase, and 35 of these patients were followed up to the late phase after symptom onset. The median platelet count (211 vs. 200 × 10(9)  L(-1) ; P = 0.03) and the median percentage of lymphocyte-platelet complexes was higher in early symptomatic than asymptomatic patients (2.8 vs. 2.4%; P = 0.001). The percentage of lymphocyte-platelet complexes was higher in early symptomatic than in asymptomatic patients with ≥ 70% carotid stenosis (P = 0.0005) and symptomatic patients recruited within 7 days of symptom onset (P = 0.028). Complete TCD data were available in 25 asymptomatic, 31 early phase symptomatic and 27 late phase symptomatic patients. Twelve per cent of asymptomatic vs. 32% of early phase symptomatic (P = 0.02) and 19% of late phase symptomatic patients (P = 0.2) were MES positive. Early symptomatic MES-negative patients had a higher percentage of lymphocyte-platelet complexes than asymptomatic MES-negative patients (2.8 vs. 2.3%; P = 0.0085). DISCUSSION: Recently, symptomatic carotid stenosis patients have had higher platelet counts (potentially reflecting increased platelet production, mobilization or reduced clearance) and platelet activation status than asymptomatic patients. MES were more frequently detected in early symptomatic than asymptomatic patients, but the differences between late symptomatic and asymptomatic groups were not significant. Increased lymphocyte-platelet complex formation in recently symptomatic vs. asymptomatic MES-negative patients indicates enhanced platelet activation in this early symptomatic subgroup. Platelet biomarkers, in combination with TCD, have the potential to aid risk-stratification in asymptomatic and symptomatic carotid stenosis patients.

Neurosarcoidosis-related intracranial haemorrhage: three new cases and a systematic review of the literature.

BACKGROUND AND PURPOSE: Intracranial haemorrhage in neurosarcoidosis (NS-ICH) is rare, poorly understood and the diagnosis of NS may not be immediately apparent. METHODS: The clinical features of three new NS-ICH cases are described including new neuropathological findings and collated with cases from a systematic literature review. CASES: (i) A 41-year-old man with headaches, hypoandrogenism and encephalopathy developed a cerebellar haemorrhage. He had neuropathological confirmation of NS with biopsy-proven angiocentric granulomata and venous disruption. He responded to immunosuppressive therapy. (ii) A 41-year-old man with no history of hypertension was found unconscious. A subsequently fatal pontine haemorrhage was diagnosed. Liver biopsy revealed sarcoid granulomas. (iii) A 36-year-old man with raised intracranial pressure headaches presented with a seizure and a frontal haemorrhage. Hilar lymph node biopsy confirmed sarcoidosis, and he was treated successfully. Systematic review: Twelve other published cases were identified and collated with our cases. Average age was 36 years and M:F = 2.3:1; 46% presented with neurological symptoms and 31% had CNS-isolated disease. Immediate symptoms of ICH were acute/worsening headache or seizures (60%). ICH was supratentorial (62%), infratentorial (31%) or subarachnoid (7%). Forty percent had definite NS, 53% probable NS and 7% possible NS (Zajicek criteria). Antigranulomatous/immunosuppressive therapy regimens varied and 31% died. CONCLUSIONS: This series expands our knowledge of the pathology of NS-ICH, which may be of arterial or venous origin. One-third have isolated NS. Clinicians should consider NS in young-onset ICH because early aggressive antigranulomatous therapy may improve outcome.

Platelet activation, function, and reactivity in atherosclerotic carotid artery stenosis: a systematic review of the literature.

An important proportion of transient ischemic attack or ischemic stroke is attributable to moderate or severe (50-99%) atherosclerotic carotid stenosis or occlusion. Platelet biomarkers have the potential to improve our understanding of the pathogenesis of vascular events in this patient population. A detailed systematic review was performed to collate all available data on ex vivo platelet activation and platelet function/reactivity in patients with carotid stenosis. Two hundred thirteen potentially relevant articles were initially identified; 26 manuscripts met criteria for inclusion in this systematic review. There was no consistent evidence of clinically informative data from urinary or soluble blood markers of platelet activation in patients with symptomatic moderate or severe carotid stenosis who might be considered suitable for carotid intervention. Data from flow cytometry studies revealed evidence of excessive platelet activation in patients in the early, sub-acute, or late phases after transient ischemic attack or stroke in association with moderate or severe carotid stenosis and in asymptomatic moderate or severe carotid stenosis compared with controls. Furthermore, pilot data suggest that platelet activation may be increased in recently symptomatic than in asymptomatic severe carotid stenosis. Excessive platelet activation and platelet hyperreactivity may play a role in the pathogenesis of first or subsequent transient ischemic attack or stroke in patients with moderate or severe carotid stenosis. Larger longitudinal studies assessing platelet activation status with flow cytometry and platelet function/reactivity in symptomatic vs. asymptomatic carotid stenosis are warranted to improve our understanding of the mechanisms responsible for transient ischemic attack or stroke.

High on-treatment platelet reactivity on commonly prescribed antiplatelet agents following transient ischaemic attack or ischaemic stroke: results from the Trinity Antiplatelet Responsiveness (TRAP) study.

BACKGROUND AND PURPOSE: The prevalence of ex vivo 'high on-treatment platelet reactivity' (HTPR) to antiplatelet regimens in patients with ischaemic cerebrovascular disease (CVD) is uncertain. METHODS: HTPR was assessed with PFA-100 collagen-epinephrine (C-EPI) and collagen-ADP (C-ADP) cartridges. Platelet activation (CD62P, CD63 and leucocyte-platelet complex formation) was assessed with whole-blood flow cytometry. Patients were assessed at baseline [≤ 4 weeks of transient ischaemic attack (TIA) or ischaemic stroke], and at 14 days and ≥ 90 days after changing treatment from (i) no medication to aspirin monotherapy (N = 26) or (ii) aspirin to clopidogrel monotherapy (N = 22). HTPR was defined in a novel, 'longitudinal fashion' as failure to prolong relevant closure times compared with the patient's 'baseline value' before he/she underwent an antiplatelet change by more than twice the coefficient of variation of the assay. RESULTS: (i) C-EPI closure times increased at 14 days and 90 days after commencing aspirin (P = 0.002); 24% at 14 days and 18% at 90 days demonstrated HTPR on aspirin. (ii) C-ADP closure times increased at 14 days (P = 0.001) but not 90 days (P = 0.09) after changing from aspirin to clopidogrel; 41% at 14 days, and 35% at 90 days demonstrated HTPR on clopidogrel. Platelet activation was unaffected by aspirin (P = 0.09). The percentage neutrophil-platelet complexes decreased at 14 days (P = 0.02), but this reduction was not maintained 90 days after changing to clopidogrel (P = 0.3). No patient had a recurrent vascular event during prospective follow-up. CONCLUSIONS: Longitudinal definitions of HTPR in patients with ischaemic CVD who are undergoing a change in antiplatelet therapy have the potential to provide more clinically meaningful information than traditional 'cross-sectional definitions' of HTPR which are usually based on the comparison of patients' values with those in healthy controls. Using our novel, longitudinal definition of HTPR, the PFA-100 could be used to monitor ex vivo responsiveness to aspirin, and larger, prospective studies are warranted to assess the clinical predictive value of this and other platelet function tests in patients with ischaemic CVD.

Repeated measurement of mechanical properties in viable osteochondral explants following a single blunt impact injury.

The objective of this work was to develop a method for repeated same-site measurement of mechanical properties suitable for the detection of degenerative changes in a biologically active explant model after a single blunt impact injury. Focal blunt impact injuries to articular surfaces lead to local cartilage degeneration and loss of mechanical properties. We employed a repeated measurement methodology to determine variations in mechanical same-site properties before and after injury in living cartilage, with the hypothesis that normalization with initial mechanical properties may provide a clearer evaluation of impact effects and improve our understanding of the biologic responses to impact injury. Bovine osteochondral explants were cultured for up to 14 days after impact injury. Indentation tests were performed before and after impact injury to assess relative changes in mechanical properties. Creep strain increased significantly in impacted explants after 7 days and in both impacted and control explants after 14 days. Further analysis at 14 days revealed decreases in stretch factor beta, creep time constant and local compressive modulus. A repeated measures methodology reliably detected changes in the mechanical behaviour of viable osteochondral explants after a single impact injury.