Brain imaging factors associated with progression of subcortical hyperintensities in CADASIL over 2-year follow-up.

BACKGROUND AND PURPOSE: Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a cerebral small vessel disease manifesting with stroke, migraine and dementia in adults. The disease displays significant phenotypic variability that is incompletely explained. Early abnormalities in vascular function have been shown in animal models. We postulated that studying changes in vascular function may offer insights into disease progression. METHODS: Twenty-two subjects with CADASIL [50% female, 50 (±11) years] from 19 pedigrees were included in a longitudinal multimodality study using brain magnetic resonance imaging (MRI), clinical measures, neuropsychology and measures of peripheral vascular function. MRI studies included measurement of structural brain changes, cerebral blood flow (CBF) and cerebrovascular reactivity by arterial spin labelling and a CO2 respiratory challenge. RESULTS: Over 2 years, new stroke or transient ischaemic attack (TIA) occurred in five (23%) subjects and new significant disability in one (5%). There were significant increases in number of lacunes, subcortical hyperintensity volume and microbleeds, and a decrease in brain volume. CBF declined by 3.2 (±4.5) ml/100 g/min over 2 years. CBF and carotid-femoral pulse wave velocity at baseline predicted change in subcortical hyperintensity volume at follow-up. Carotid intima-media thickness and age predicted brain atrophy. Baseline CBF was lower in subjects who showed a decline in attention and working memory. CONCLUSIONS: Cerebral blood flow predicts radiological progression of hyperintensities and thus is a potential biomarker of disease progression in CADASIL. Over 2 years, there were changes in several relevant imaging biomarkers (CBF, brain volume, lacunes, microbleeds and hyperintensity volume). Future studies in CADASIL should consider assessment of CBF as prognostic factor.

Polypharmacy, functional outcome and treatment effect of intravenous alteplase for acute ischaemic stroke.

BACKGROUND AND PURPOSE: Polypharmacy is an important challenge in clinical practice. Our aim was to determine the effect of polypharmacy on functional outcome and treatment effect of alteplase in acute ischaemic stroke. METHODS: This was a post hoc analysis of the randomized, placebo-controlled WAKE-UP trial of magnetic resonance imaging guided intravenous alteplase in unknown onset stroke. Polypharmacy was defined as an intake of five or more medications at baseline. Comorbidities were assessed by the Charlson Comorbidity Index (CCI). The primary efficacy variable was favourable outcome defined by a score of 0-1 on the modified Rankin Scale at 90 days. Logistic regression analysis was used to test for an association of polypharmacy with functional outcome, and for interaction of polypharmacy and the effect of thrombolysis. RESULTS: Polypharmacy was present in 133/503 (26%) patients. Patients with polypharmacy were older (mean age 70 vs. 64 years; p < 0.0001) and had a higher score on the National Institutes of Health Stroke Scale at baseline (median 7 vs. 5; p = 0.0007). A comorbidity load defined by a CCI score ≥ 2 was more frequent in patients with polypharmacy (48% vs. 8%; p < 0.001). Polypharmacy was associated with lower odds of favourable outcome (adjusted odds ratio 0.50, 95% confidence interval 0.30-0.85; p = 0.0099), whilst the CCI score was not. Treatment with alteplase was associated with higher odds of favourable outcome in both groups, with no heterogeneity of treatment effect (test for interaction of treatment and polypharmacy, p = 0.29). CONCLUSION: In stroke patients, polypharmacy is associated with worse functional outcome after intravenous thrombolysis independent of comorbidities. However, polypharmacy does not interact with the beneficial effect of alteplase.

Effect of atrial fibrillation on endovascular thrombectomy for acute ischemic stroke. A meta-analysis of individual patient data from six randomised trials: Results from the HERMES collaboration.

BACKGROUND: Atrial fibrillation is an important risk factor for ischemic stroke, and is associated with an increased risk of poor outcome after ischemic stroke. Endovascular thrombectomy is safe and effective in acute ischemic stroke patients with large vessel occlusion of the anterior circulation. This meta-analysis aims to investigate whether there is an interaction between atrial fibrillation and treatment effect of endovascular thrombectomy, and secondarily whether atrial fibrillation is associated with worse outcome in patients with ischemic stroke due to large vessel occlusion. METHODS: Individual patient data were from six of the recent randomised clinical trials (MR CLEAN, EXTEND-IA, REVASCAT, SWIFT PRIME, ESCAPE, PISTE) in which endovascular thrombectomy plus standard care was compared to standard care alone. Primary outcome measure was the shift on the modified Rankin scale (mRS) at 90 days. Secondary outcomes were functional independence (mRS 0-2) at 90 days, National Institutes of Health Stroke Scale score at 24 h, symptomatic intracranial hemorrhage and mortality at 90 days. The primary effect parameter was the adjusted common odds ratio, estimated with ordinal logistic regression (shift analysis); treatment effect modification of atrial fibrillation was assessed with a multiplicative interaction term. RESULTS: Among 1351 patients, 447 patients had atrial fibrillation, 224 of whom were treated with endovascular thrombectomy. We found no interaction of atrial fibrillation with treatment effect of endovascular thrombectomy for both primary (p-value for interaction: 0.58) and secondary outcomes. Regardless of treatment allocation, we found no difference in primary outcome (mRS at 90 days: aOR 1.11 (95% CI 0.89-1.38) and secondary outcomes between patients with and without atrial fibrillation. CONCLUSION: We found no interaction of atrial fibrillation on treatment effect of endovascular thrombectomy, and no difference in outcome between large vessel occlusion stroke patients with and without atrial fibrillation.

Pulse pressure variability is associated with unfavorable outcomes in acute ischaemic stroke patients treated with intravenous thrombolysis.

BACKGROUND AND PURPOSE: Blood pressure (BP) variability has been associated with worse neurological outcomes in acute ischaemic stroke (AIS) patients receiving treatment with intravenous thrombolysis (IVT). However, no study to date has investigated whether pulse pressure (PP) variability may be a superior indicator of the total cardiovascular risk, as measured by clinical outcomes. METHODS: Pulse pressure variability was calculated from 24-h PP measurements following tissue plasminogen activator bolus in AIS patients enrolled in the Combined Lysis of Thrombus using Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization (CLOTBUST-ER) trial. The outcomes of interest were the pre-specified efficacy and safety end-points of CLOTBUST-ER. All associations were adjusted for potential confounders in multivariable regression models. RESULTS: Data from 674 participants was analyzed. PP variability was identified as the BP parameter with the most parsimonious fit in multivariable models of all outcomes, and was independently associated (P < 0.001) with lower likelihood of both 24-h neurological improvement and 90-day independent functional outcome. PP variability was also independently related to increased odds of any intracranial bleeding (P = 0.011) and 90-day mortality (P < 0.001). Every 5-mmHg increase in the 24-h PP variability was independently associated with a 36% decrease in the likelihood of 90-day independent functional outcome (adjusted odds ratio 0.64, 95% confidence interval 0.52-0.80) and a 60% increase in the odds of 90-day mortality (adjusted odds ratio 1.60, 95% confidence interval 1.23-2.07). PP variability was not associated with symptomatic intracranial bleeding at either 24 or 36 h after IVT administration. CONCLUSIONS: Increased PP variability appears to be independently associated with adverse short-term and long-term functional outcomes of AIS patients treated with IVT.

Baseline factors associated with early and late death in intracerebral haemorrhage survivors.

BACKGROUND AND PURPOSE: The aim of this study was to determine whether early and late death are associated with different baseline factors in intracerebral haemorrhage (ICH) survivors. METHODS: This was a secondary analysis of the multicentre prospective observational CROMIS-2 ICH study. Death was defined as 'early' if occurring within 6 months of study entry and 'late' if occurring after this time point. RESULTS: In our cohort (n = 1094), there were 306 deaths (per 100 patient-years: absolute event rate, 11.7; 95% confidence intervals, 10.5-13.1); 156 were 'early' and 150 'late'. In multivariable analyses, early death was independently associated with age [per year increase; hazard ratio (HR), 1.05, P = 0.003], history of hypertension (HR, 1.89, P = 0.038), pre-event modified Rankin scale score (per point increase; HR, 1.41, P < 0.0001), admission National Institutes of Health Stroke Scale score (per point increase; HR, 1.11, P < 0.0001) and haemorrhage volume >60 mL (HR, 4.08, P < 0.0001). Late death showed independent associations with age (per year increase; HR, 1.04, P = 0.003), pre-event modified Rankin scale score (per point increase; HR, 1.42, P = 0.001), prior anticoagulant use (HR, 2.13, P = 0.028) and the presence of intraventricular extension (HR, 1.73, P = 0.033) in multivariable analyses. In further analyses where time was treated as continuous (rather than dichotomized), the HR of previous cerebral ischaemic events increased with time, whereas HRs for Glasgow Coma Scale score, National Institutes of Health Stroke Scale score and ICH volume decreased over time. CONCLUSIONS: We provide new evidence that not all baseline factors associated with early mortality after ICH are associated with mortality after 6 months and that the effects of baseline variables change over time. Our findings could help design better prognostic scores for later death after ICH.

Atherosclerotic Carotid Plaque Composition: A 3T and 7T MRI-Histology Correlation Study.

BACKGROUND AND PURPOSE: Carotid artery atherosclerotic plaque composition may influence plaque stability and risk of thromboembolic events, and noninvasive plaque imaging may therefore permit risk stratification for clinical management. Plaque composition was compared using noninvasive in vivo (3T) and ex vivo (7T) MRI and histopathological examination. METHODS: Thirty-three endarterectomy cross-sections, from 13 patients, were studied. The data sets consisted of in vivo 3T MRI, ex vivo 7T MRI, and histopathology. Semiautomated segmentation methods were used to measure areas of different plaque components. Bland-Altman plots and mean difference with 95% confidence interval were carried out. RESULTS: There was general quantitative agreement between areas derived from semiautomated segmentation of MRI data and histology measurements. The mean differences and 95% confidence bounds in the relative to total plaque area between 3T versus Histology were: fibrous tissue 4.99%(-4.56 to 14.56), lipid-rich/necrotic core (LR/NC) with hemorrhage -1.81%(-14.11 to 10.48), LR/NC without hemorrhage -2.43%(-13.04 to 8.17), and calcification -3.18%(-11.55 to 5.18). The mean differences and 95% confidence bounds in the relative to total plaque area between 7T and histology were: fibrous tissue 3.17%(-3.17 to 9.52), LR/NC with hemorrhage -0.55%(-9.06 to 7.95), LR/NC without hemorrhage -12.62%(-19.8 to -5.45), and calcification -2.43%(-9.97 to 4.73). CONCLUSIONS: This study provides evidence that semiautomated segmentation of 3T/7T MRI techniques can help to determine atherosclerotic plaque composition. In particular, the high resolution of ex vivo 7T data was able to highlight greater detail in the atherosclerotic plaque composition. High-field MRI may therefore have advantages for in vivo carotid plaque MRI.

Applying the resources and supports in self-management framework to examine ophthalmologist-patient communication and glaucoma medication adherence.

Little is known about how ophthalmologist-patient communication over time is associated with glaucoma patient long-term adherence. The purpose of our study was to examine the association between provider use of components of the resources and supports in self-management model when communicating with patients and adherence to glaucoma medications measured electronically over an 8-month period. In this longitudinal prospective cohort study, the main variables studied were ophthalmologist communication-individualized assessment, collaborative goal setting and skills enhancement. Patients with glaucoma who were newly prescribed or on glaucoma medications were recruited from six ophthalmology clinics. Patients' baseline and next follow-up visits were videotape-recorded. Patients were interviewed after their visits. Patients used medication event monitoring systems (MEMS) for 8 months after enrollment into the study, and adherence was measured electronically using MEMS for 240 days after their visits. Two hundred and seventy-nine patients participated. Patient race and regimen complexity were negatively associated with glaucoma medication adherence over an 8-month period. Provider communication behaviors, including providing education and positive reinforcement, can improve patient adherence to glaucoma medications over an 8-month period.

Changing clinical patterns and increasing prevalence in CADASIL.

OBJECTIVES: CADASIL is a monogenic small vessel vasculopathy causing recurrent stroke. Early descriptions suggested dementia and disability were common from the 5th decade but there is evidence of marked phenotypic variability. We investigated the prevalence and clinical features of CADASIL in the west of Scotland. METHODS: We undertook a retrospective review of clinical records of patients with confirmed CADASIL identified through a specialist clinic. Patients were divided to examine the effect of date of diagnosis on clinical outcomes and the characteristics at different ages. The location of pedigree members was used to estimate prevalence. RESULTS: Twenty-one different CADASIL-causing NOTCH3 mutations were identified in 49 pedigrees (61% in exon 4). Disease prevalence in Glasgow was 4.6/100,000 adults. Mutation prevalence was estimated at 10.7/100,000 population. Median age at first stroke in women (57 years) was higher than previous estimates, and stroke age in men was higher in patients diagnosed more recently (pre 2006 46 years, post 2006 56 years, P=0.034). In patients over 58 years of age, 13/34 (38%) were living independently and 17/28 (61%) were mobile without aids when last seen. CONCLUSIONS: CADASIL prevalence is at least 4.6 per 100,000 adults. Median age of first stroke may be older than previously thought. Clinicians should consider CADASIL in the differential diagnosis even in older patients with stroke.

Systematic review of methods for assessing leptomeningeal collateral flow.

BACKGROUND AND PURPOSE: The importance of LMF in the outcome after acute ischemic stroke is increasingly recognized, but imaging presents a wide range of options for identification of collaterals and there is no single system for grading collateral flow. The aim of this study was to systematically review the literature on the available methods for measuring LMF adequacy. MATERIALS AND METHODS: We performed a systematic review of Ovid, MEDLINE, and Embase databases for studies in which flow in the leptomeningeal collateral vessels was evaluated. Imaging technique, grading scale, and reliability assessment for collateral flow measurement were recorded. RESULTS: We found 81 publications describing 63 methods for grading collateral flow on the basis of conventional angiography (n = 41), CT (n = 7), MR imaging (n = 9), and transcranial Doppler (n = 6). Inter- and/or intraobserver agreement was assessed in only 8 publications. CONCLUSIONS: There is inconsistency in how LMF is graded, with a variety of grading scales and imaging modalities being used. Consistency in evaluating collateral flow at baseline is required for the impact of collateral flow to be fully appreciated.

Early carotid endarterectomy following thrombolysis in the hyperacute treatment of stroke.

BACKGROUND: Thrombolysis with intravenous recombinant tissue plasminogen activator improves the probability of complete neurological recovery if given promptly following the onset of acute ischaemic stroke. Carotid endarterectomy (CEA) can reduce the risk of further embolic stroke in selected patients and is most effective within 14 days of the incident event. The safety of surgery so soon after thrombolysis is unknown. The aim of this study was to report the immediate outcomes of this management strategy early in the unit experience and to encourage pooling of data, recognizing that this will be an uncommon procedure even in busy stoke units with an active lysis programme. METHODS: Data were extracted from two prospectively collected databases, and included patient demographics, type of stroke, type and timing of surgical procedure, and immediate outcome. On presentation with a stroke, all patients underwent urgent computed tomography (CT) of the brain. Those eligible received thrombolysis according to the unit protocol. They underwent CT angiography 24 h after thrombolysis and patients with a severe carotid stenosis had surgery. RESULTS: Ten of a cohort of 450 patients who had received lysis underwent CEA. Seven of these were women and eight of the procedures were carried out under local anaesthetic. Surgery was performed a median of 8 (range 2-23) days after the index event; there were no major complications. CONCLUSION: Few patients with acute stroke are eligible, but CEA performed soon after thrombolytic therapy for stroke appears to be safe.

Do iodinated contrast agents impair fibrinolysis in acute stroke? A systematic review.

BACKGROUND AND PURPOSE: In vitro and nonhuman in vivo studies demonstrating impaired fibrinolysis of thrombus by thrombolytic agents in the presence of iodinated contrast media (ICM) have prompted concern regarding the clinical use of ICM. A systematic review and meta-analysis were performed to investigate the proportion of patients with acute stroke experiencing recanalization after thrombolytic therapy in whom ICM were administered compared with those in whom they were not. MATERIALS AND METHODS: Embase and Medline searches identified studies reporting recanalization rates in acute ischemic anterior circulation stroke. Pooled proportions of patients who recanalized were calculated with a random-effects model, and studies involving contrast (CS) were compared with those without (NCS). RESULTS: Six studies were found in which ICM were administered, and 12 studies, in which they were not. Studies were statistically heterogeneous. Combined pooled proportions and 95% confidence intervals (CI) for recanalization in unselected CS and NCS were 53% (36%-70%) and 61% (52%-71%), respectively. In a subgroup analysis in which only middle cerebral artery occlusions were considered, the pooled proportions in CS (n = 3 studies) and NCS (n = 9 studies) were 66% (95% CI, 49%-82%; I(2), 0%) and 63% (CI, 52%-74%; I(2), 82.5%). CONCLUSIONS: Recanalization rates were not significantly different in patients who received iodinated contrast agents in clinical studies. A randomized trial to test whether ICM affect recanalization would require a prohibitively large number of subjects.

Thrombolytic therapy for acute stroke in the United Kingdom: experience from the safe implementation of thrombolysis in stroke (SITS) register.

AIM: To describe the United Kingdom (UK) experience with thrombolytic therapy with intravenous alteplase (rt-PA) for stroke, as captured by the Implementation of Thrombolysis in Stroke (SITS) project. METHODS: The multinational Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was an observational study to assess the safety and efficacy of thrombolytic therapy, when administered within the first 3 h after onset of ischaemic stroke. SITS-MOST was embedded within the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), an internet-based, international monitoring registry for auditing the safety and efficacy of routine therapeutic use of thrombolysis in acute ischaemic stroke. We performed an analysis of data contributed to SITS-MOST and SITS-ISTR from UK centres. RESULTS: A total of 614 patients received thrombolysis for stroke between December 2002 and April 2006, 327 were registered to SITS-MOST and 287 to SITS-ISTR. Thirty-one centres treated patients in the UK, of which 23 registered patients in both SITS-MOST and SITS-ISTR and eight solely to SITS-ISTR. The median age from the UK SITS-MOST was identical to the non-UK SITS-MOST register: 68 years (IQR 59-75). The majority (96.1%) of patients from the UK were treated between 8.00 a.m. and 9.00 p.m., and only 18.4% were treated on weekend days, reflecting the difficulties of maintaining provision of a thrombolytic service out of hours. Median onset-to-treatment-time was 155 min (IQR 130-170 min) for the UK, compared to 140 min (IQR 114-165 min) for the non-UK SITS-MOST group (P < 0.001). UK SITS-MOST patients at baseline had more severe stroke in comparison with non-UK patients [median NIHSS 14.5 (IQR 9-19) vs. 12 (IQR 8-17) (P < 0.001)]. Forty-eight percent of UK patients achieved mRS of 0-2 (independence), compared to 55% of the non-UK SITS-MOST register. There was no significant difference in symptomatic intracerebral haemorrhage rate in the UK compared with the non-UK SITS-MOST patients [2.5% (95% CI 1.3-4.8) vs. 1.7% (95% CI 1.4-2.0) P = 0.28]. In the multivariate analysis, there was no statistically significant difference in any outcome between UK and non-UK SITS-MOST patients. CONCLUSION: Thrombolytic therapy for stroke has been implemented successfully at a small number of UK stroke centres, with patchy provision throughout the country. The low frequency of treatment out with office hours suggests deficient infrastructure to support delivery. UK patients tended to be more severely affected at baseline and to be treated later. Outcomes are comparable to those seen at the non-UK SITS centres.

Health literacy and vision-related quality of life.

BACKGROUND: Non-visual factors influence a person's vision-related quality of life (VRQoL). The purpose of this study was to assess the relationship between health literacy and VRQoL in glaucoma patients. METHODS: One hundred and ninety-five subjects with open-angle glaucoma participated in a cross-sectional patient survey and chart review. Subjects were administered a test of health literacy, an assessment of physical and mental well-being, and an assessment of VRQoL, the National Eye Institute 25-Item Visual Function Questionnaire (VFQ-25). Charts were reviewed for visual acuity and visual field results. RESULTS: In univariate analyses, older age (p<0.001), non-White race (p<0.001), worse visual acuity (p<0.001), worse visual field scores (p<0.001), lower level of education (p<0.001), worse health literacy (p<0.001) and worse score on the mental health component of the SF-12 (p = 0.005) were associated with worse VFQ-25 scores. In multivariate analyses, only older age was associated with worse total VFQ-25 scores (p<0.001), although the association between health literacy and the VFQ subscale of dependency remained significant (p = 0.04). CONCLUSIONS: Individuals with a lower health literacy do not appear to have a worse overall VRQoL compared with those with a higher literacy, but worse health literacy is associated with increased dependency.

Visual evaluation of perfusion computed tomography in acute stroke accurately estimates infarct volume and tissue viability.

OBJECTIVE: To establish the validity of visual interpretation of immediately processed perfusion computed tomography (CT) maps in acute stroke for prediction of final infarction. METHODS: Perfusion CT studies acquired prospectively were reprocessed within six hours of stroke onset using standard CT console software. Four contiguous 5 mm thick images were obtained and maps of time to peak (TTP) and cerebral blood volume (CBV) generated. Volumes of lesions identified only by visual inspection were measured from manually drawn regions of interest. Volumes of tissue with prolonged TTP or reduced CBV were compared with independently calculated volume of infarction on non-contrast CT (NCCT) at 24-48 hours, and with clinical severity using the NIHSS score. Arterial patency at 24-48 h was included in analyses. RESULTS: Studies were analysed from 17 patients 150 minutes (median) after stroke onset. Volume of tissue with prolonged TTP correlated with initial NIHSS (r = 0.62, p = 0.009), and with NCCT final infarct volume when arterial occlusion persisted (r = 0.953, p = 0.012). Volume of tissue with reduced CBV correlated with final infarct volume if recanalisation occurred (r = 0.835, p = 0.001). Recanalisation was associated with lower 24 h NIHSS score (6 (IQR, 5 to 9.5) v 19 (18 to 26), p = 0.027), and in 10 patients given rtPA for MCA M1 occlusion, with lower infarct volume (73 v 431 ml, p = 0.002). CONCLUSIONS: Visual evaluation of TTP and CBV maps generated by standard perfusion CT software correlated with 24-48 hour CT infarct volumes. Comparison of TTP and CBV maps yields information on tissue viability. Perfusion CT represents a practical technique to aid acute clinical decision making. Recanalisation was a crucial determinant of clinical and radiological outcome.

Is inadequate family history a barrier to diagnosis in CADASIL?

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) has typical clinical features that include stroke, migraine, mood disturbances and cognitive decline. However, misdiagnosis is common. We hypothesized that family history is poorly elicited in individuals presenting with features of CADASIL and that enquiry into family history of all four cardinal manifestations of CADASIL is superior to elicitation of family history of premature stroke alone in raising the diagnostic possibility of CADASIL. MATERIALS AND METHODS: Retrospective review of family histories at presentation in 40 individuals with confirmed CADASIL was performed through structured interview in a Neurovascular Genetics clinic (182 first-degree and 242 second-degree relatives identified). Family history obtained from structured interview was compared to family history initially documented at presentation. RESULTS: At initial presentation, 30% of individuals were inaccurately documented to have no family history of significant neurological illness. Thirty-five per cent of patients had an initial alternative diagnosis. Initial inaccurate documentation of negative family history was more frequent in individuals with an initial alternative diagnosis. After structured interviews, 34% of 182 first-degree and 35% of 242 second-degree relatives of CADASIL patients had history of stroke (16% of first-degree relatives had stroke before the age of 50 years). Forty-three per cent of first-degree and 28% of second-degree relatives had migraine, mood disturbance or cognitive decline. CONCLUSIONS: A false-negative family history was commonly documented in individuals presenting with features of CADASIL and was associated with initial misdiagnosis. Restriction of family history to premature stroke alone is probably inadequate to identify affected CADASIL pedigrees.

Intravenous thrombolysis for acute ischaemic stroke: preliminary experience with recombinant tissue plasminogen activator in the UK.

OBJECTIVE: To present the preliminary experience of implementing intravenous thrombolytic therapy for acute ischaemic stroke in three UK stroke centres. BACKGROUND: Recombinant tissue plasminogen activator for ischaemic stroke received approval from UK regulatory authorities in April 2003. Since 1997, a small number of UK centres had used thrombolytic therapy in highly selected stroke patients. We present the early experience of that treatment in Glasgow and Newcastle. DESIGN: Patients were selected and treated in accordance with the American Heart Association guidelines. Additionally, radiologic criteria employed in the European-Australasian Acute Stroke Studies were applied. National Institutes of Health Stroke Scale (NIHSS) scores were measured on admission, and Modified Rankin Scale (MRS) scores were assessed at 3 months for all patients with stroke treated prior to initiation of the Safe Implementation of Thrombolysis in Stroke monitoring program for implementation of thrombolysis in stroke in April 2001. Intracranial and systemic haemorrhagic complications were recorded. RESULTS: 120 patients received thrombolytic treatment (approximately 1% of all admissions with presumed stroke). Mean age was 69 years (range 22-93) and initial median NIHSS score was 17 (range 3-31). In the two centres for which temporal data were available, the mean delay between symptom onset and treatment was 139 min (range 20-185). Sixteen episodes of cerebral haemorrhage or haemorrhagic transformation of any degree occurred, of which 5 (4%) were symptomatic. One patient deteriorated and died before repeat CT imaging could be performed. One non-fatal episode of systemic bleeding occurred. One patient was lost to follow-up. At 3 months, 31% of recipients had achieved good (MRS 0-1) outcome, 22% moderate (MRS 2-3) outcome and 21% (MRS 4-5) poor outcome. Twenty-one per cent died within 3 months of stroke. Observed frequency of bleeding complications and protocol violations (6%) was similar to those reported elsewhere. CONCLUSION: A small proportion of stroke patients received thrombolytic treatment. Patients treated were more severely affected than in other published European and North American series. Outcomes and complications were consistent with experience elsewhere.

The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations of the Notch3 gene on 19p13. Varying phenotypic expression leads to under recognition and misdiagnosis. Prevalence therefore remains uncertain. We sought to estimate the prevalence of CADASIL in the west of Scotland. METHODS: A register for CADASIL was established at a regional neurosciences centre in 2002. All patients with genetically (exons 3, 4, 5, and 6) or histologically confirmed CADASIL residing in two defined administrative health areas were identified. Pedigree members at varying risk of carrying the mutation were also identified and the number of probable Notch3 mutation carriers in the defined population was predicted. Prevalence was calculated for definite CADASIL cases, with and without probable carrier numbers, based upon adult population figures from the 2002 national census. RESULTS: Twenty two individuals from seven pedigrees with confirmed CADASIL and resident in the defined geographical area were identified, yielding a prevalence of 1.98 (95% confidence interval 1.24-3.00) per 100 000 adults. An additional 37 individuals were predicted to be carriers of the Notch3 mutation, yielding a probable mutation prevalence of 4.14 (3.04-5.53) per 100,000 adults. CONCLUSIONS: The prevalence of genetically proven CADASIL was 1.98 per 100,000 adults in the defined population. This figure underestimates disease burden.

Magnesium for acute stroke (Intravenous Magnesium Efficacy in Stroke trial): randomised controlled trial.

BACKGROUND: Magnesium is neuroprotective in animal models of stroke, and findings of small clinical pilot trials suggest potential benefit in people. We aimed to test whether intravenous magnesium sulphate, given within 12 h of stroke onset, reduces death or disability at 90 days. METHODS: 2589 patients were randomised within 12h of acute stroke to receive 16 mmol MgSO4 intravenously over 15 min and then 65 mmol over 24 h, or matching placebo. Primary outcome was a global endpoint statistic expressed as the common odds ratio for death or disability at day 90. Secondary outcomes were mortality and death or disability, variously defined as Barthel score less than 95, Barthel score less than 60, and modified Rankin scale more than 1. Predefined subgroup analyses were for the primary endpoint in patients in whom treatment commenced within 6 h versus after 6 h, ischaemic versus non-ischaemic strokes, and cortical stroke syndromes versus non-cortical strokes. Intention-to-treat and efficacy analyses were done. FINDINGS: The efficacy dataset included 2386 patients. Primary outcome was not improved by magnesium (odds ratio 0.95, 95% CI 0.80-1.13, p=0.59). Mortality was slightly higher in the magnesium-treated group than in the placebo group (hazard ratio 1.18, 95% CI 0.97-1.42, p=0.098). Secondary outcomes did not show any treatment effect. Planned subgroup analyses showed benefit of magnesium in non-cortical strokes (p=0.011) whereas greater benefit had been expected in the cortical group. INTERPRETATION: Magnesium given within 12 h of acute stroke does not reduce the chances of death or disability significantly, although it may be of benefit in lacunar strokes.