Neuromelanin-MRI to Quantify and Track Nigral Depigmentation in Parkinson's Disease: A Multicenter Longitudinal Study Using Template-Based Standardized Analysis.

BACKGROUND: Clinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin-magnetic resonance imaging (NM-MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings. OBJECTIVES: The aim was to investigate the diagnostic accuracy of NM-MRI in early PD in a multiprotocol setting and to determine and compare serial NM-MRI changes in PD and controls. METHODS: In this longitudinal case-control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template-based analysis was applied for subregional substantia nigra NM-MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed. RESULTS: All NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity. CONCLUSIONS: We demonstrate that NM-MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker-enabled clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Relationship between poststroke cognition, baseline factors, and functional outcome: data from "efficacy of nitric oxide in stroke" trial.

BACKGROUND: Poststroke cognitive impairment is common and identification of prognostic factors associated with it and its relationship with other functional outcomes may help in developing preventative strategies. METHODS: Previously independent patients with acute stroke, enrolled into the ongoing "Efficacy of Nitric Oxide in Stroke" trial, were assessed by telephone on day 90 for cognitive impairment using modified versions of "Mini Mental State Examination" (MMSE-M) and "Telephone Instrument for Cognitive Status" (TICS-M) scales and category fluency. The relationship of cognitive impairment with baseline prognostic factors and other functional outcomes at day 90 were studied. RESULTS: The analysis included 1572 patients, mean age 69 years (standard deviation, 12), and female 40%. By 90 days, 246 patients had died, and cognitive impairment was present in 38%. Increasing age, stroke severity, heart rate, and presence of cerebral atrophy on baseline neuroimaging were associated with cognitive impairment (all P < .001). Hypertension and atrial fibrillation were also associated with category fluency and MMSE-M, respectively. Cognition was significantly related to other functional outcomes, TICS-M with dependency (modified Rankin Scale, rs = -.562, P < .001); disability (Barthel Index, rs = .577, P < .001); mood (Zung Depression Score, rs = -.542, P < .001); and quality of life (Euro Quality of life-5 Descriptor, rs = .519, P < .001). CONCLUSIONS: In previously independent individuals, cognitive impairment was common 3 months after stroke and related to increasing age, stroke severity, hypertension, atrial fibrillation, and cerebral atrophy on brain scanning. Cognition was related to dependency, disability, low mood, and quality of life. Hence, treatment directed toward reducing dependency might also reduce cognitive impairment.

Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial.

BACKGROUND AND PURPOSE: Granulocyte-colony stimulating factor (G-CSF) is neuroprotective in experimental stroke and mobilizes CD34(+) peripheral blood stem cells into the circulation. We assessed the safety of G-CSF in recent stroke in a phase IIb single-center randomized, controlled trial. METHODS: G-CSF (10 µg/kg) or placebo (ratio 2:1) was given SC for 5 days to 60 patients 3 to 30 days after ischemic or hemorrhagic stroke. The primary outcome was the frequency of serious adverse events. Peripheral blood counts, CD34(+) count, and functional outcome were measured. MRI assessed lesion volume, atrophy, and the presence of iron-labeled CD34(+) cells reinjected on day 6. RESULTS: Sixty patients were recruited at mean of 8 days (SD ± 5) post ictus, with mean age 71 years (± 12 years) and 53% men. The groups were well matched for baseline minimization/prognostic factors. There were no significant differences between groups in the number of participants with serious adverse events: G-CSF 15 (37.5%) of 40 versus placebo 7 (35%) of 20, death or dependency (modified Rankin Score: G-CSF 3.3 ± 1.3, placebo 3.0 ± 1.3) at 90 days, or the number of injections received. G-CSF increased CD34(+) and total white cell counts of 9.5- and 4.2-fold, respectively. There was a trend toward reduction in MRI ischemic lesion volume with respect to change from baseline in G-CSF-treated patients (P=0.06). In 1 participant, there was suggestion that labeled CD34(+) cells had migrated to the ischemic lesion. CONCLUSIONS: This randomized, double-blind, placebo-controlled trial suggests that G-CSF is safe when administered subacutely. It is feasible to label and readminister iron-labeled CD34(+) cells in patients with ischemic stroke. CLINICAL TRIAL REGISTRATION: URL: www.controlled-trials.com. Unique identifier: ISRCTN63336619.

Relationship between baseline blood pressure parameters (including mean pressure, pulse pressure, and variability) and early outcome after stroke: data from the Tinzaparin in Acute Ischaemic Stroke Trial (TAIST).

BACKGROUND AND PURPOSE: High blood pressure (BP) in acute stroke is associated independently with a poor outcome. Recent evidence suggests that other hemodynamic parameters may also be associated with outcomes following stroke. METHODS: The relationship between baseline BP, heart rate, and other hemodynamic parameters, and early outcomes were assessed using data from TAIST trial. RESULTS: Death or neurological deterioration at day 10 was associated, both in unadjusted and adjusted analyses, with systolic BP (adjusted OR, 1.02; 95% CI, 1.01-1.03), mean arterial pressure (OR, 1.02; 95% CI, 1.01-1.04), pulse pressure (OR, 1.02; 95% CI, 1.01-1.03), and BP variability (OR, 1.03; 95% CI, 1.01-1.05). Similar relationships were noted for deterioration alone, and recurrent stroke. CONCLUSIONS: Early death or neurologic deterioration, deterioration, and recurrent stroke are associated independently with high systolic BP, mean arterial pressure, pulse pressure, and BP variability. These measures offer potential therapeutic targets for improving early outcome after acute ischemic stroke.

Asymptomatic hemorrhagic transformation of infarction and its relationship with functional outcome and stroke subtype: assessment from the Tinzaparin in Acute Ischaemic Stroke Trial.

BACKGROUND AND PURPOSE: Asymptomatic hemorrhagic transformation of infarction (AHTI) is common, but its risk factors and relationship with functional outcome are poorly defined. METHODS: The analyses used data from the Tinzapararin in Acute Ischaemic Stroke Trial, a randomized controlled trial assessing tinzaparin (low molecular weight heparin) versus aspirin in 1484 patients with acute ischemic stroke. CT head scans (baseline, day 10) were adjudicated for the presence of hemorrhagic transformation. Stroke subtype was classified according to modified Trial of Org 10172 in Acute Stroke Treatment (small vessel, large vessel, cardioembolic) and the Oxfordshire Community Stroke Project (total anterior, partial anterior, lacunar, and posterior circulatory syndromes). Modified Rankin scale and Barthel Index were measured at 3 and 6 months. Analyses were adjusted for age, sex, severity, blood pressure, infarct volume, and treatment. Symptomatic hemorrhage was excluded. RESULTS: At day 10, AHTI did not differ between aspirin (300 mg; 32.8%) and medium-dose (100 IU/kg; 36.0%) and high-dose (175 IU/kg; 31.4%) tinzaparin groups (P = 0.44). Relative to lacunar stroke, AHTI on follow-up CT was significantly increased in total anterior circulation syndrome (odds ratio, 11.5; 95% CI, 7.1 to 18.7) and partial anterior circulation syndrome (odds ratio, 7.2; 95% CI, 4.5 to 11.4) stroke. Similarly, relative to small vessel disease, AHTI was increased in large vessel (odds ratio, 15.1; 95% CI, 9.4 to 24.3) and cardioembolic (odds ratio, 14.1; 95% CI, 8.5 to 23.5) stroke. After adjustment for infarct volume, the presence of AHTI was not associated with outcome at 3 or 6 months as measured by the modified Rankin Scale and Barthel Index. CONCLUSIONS: AHTI is increased in ischemic stroke with cortical syndromes and of large vessel or cardioembolic etiology. Heparin does not increase AHTI. AHTI is not associated with functional outcome.

Relationship between hyperacute blood pressure and outcome after ischemic stroke: data from the VISTA collaboration.

BACKGROUND AND PURPOSE: High blood pressure (BP) is associated independently with poor outcome after acute ischemic stroke, although in most analyses "baseline" BP was measured 24 hours or more postictus, and not during the hyperacute period. METHODS: Analyses included 1722 patients in hyperacute trials (recruitment <8 hours) from the Virtual Stroke International Stroke Trial Archive (VISTA) Collaboration. Data on BP at enrollment and after 1, 2, 16, 24, 48, and 72 hours, neurological impairment at 7 days (NIHSS), and functional outcome at 90 days (modified Rankin scale) were assessed using logistic regression models, adjusted for confounding variables; results are for 10-mm Hg change in BP. RESULTS: Mean time to enrollment was 3.7 hours (range 1.0 to 7.9). High systolic BP (SBP) was significantly associated with increased neurological impairment (odds ratio, OR 1.06, 95% confidence interval, 95% CI 1.01 to 1.12), and poor functional outcome; odds ratios for both increased with later BP measurements made at up to 24 hours poststroke. Smaller (versus larger) declines in SBP over the first 24 hours were significantly associated with poor NIHSS scores (OR 1.16, 95% CI 1.05 to 1.27) and functional outcome (OR 1.23, 95% CI 1.13 to 1.34). A large variability in SBP was also associated with poor functional outcome. CONCLUSIONS: High SBP and large variability in SBP in the hyperacute stages of ischemic stroke are associated with increased neurological impairment and poor functional outcome, as are small falls in SBP over the first 24 hours.

The relationship between baseline blood pressure and computed tomography findings in acute stroke: data from the tinzaparin in acute ischaemic stroke trial (TAIST).

BACKGROUND AND PURPOSE: High blood pressure (BP) is present in approximately 80% of patients with acute ischemic stroke and is independently associated with poor outcome. There are few data examining the relationship between admission BP and acute CT findings. METHODS: TAIST was a randomized controlled trial assessing 10 days of treatment with tinzaparin versus aspirin in 1489 patients with acute ischemic stroke (<48 hr) with admission BP of

High blood pressure in acute ischaemic stroke--broadening therapeutic horizons.

High blood pressure (BP) is present in 80% of patients with acute ischaemic stroke and is independently associated with poor outcome. Although this epidemiology suggests that BP should be lowered acutely, concerns about dysfunctional cerebral autoregulation suggest otherwise. Several small randomised trials have assessed cerebral blood flow with various antihypertensive classes and agents in acute ischaemic stroke. Overall, these studies showed no change in cerebral perfusion, although the numbers of studies and patients are limited and there are methodological problems with some trials. There are no large published randomised trials assessing outcome with BP lowering in acute stroke. Calcium channel blockers did not alter outcome after ischaemic stroke (29 trials, 7,665 patients). However, some trials, especially those testing intravenous calcium channel blockers (INWEST) or oral beta-receptor antagonists (BEST) reported real or potential hazard. In contrast, oral candesartan reduced combined vascular events in 339 patients with ischaemic stroke (ACCESS) although it had no effect on disability. The CHHIPS trial found that death was reduced in patients randomised to active treatment (labetalol, lisinopril) as compared with placebo. Two larger trials reported that glucose-potassium-insulin therapy (GIST) or magnesium (IMAGES) lowered BP but had no effect on functional outcome. The INTERACT pilot trial studied patients with intracerebral haemorrhage and found that an intensive BP-lowering regime non-significantly reduced haematoma expansion. There are four large ongoing trials examining whether to continue or stop pre-stroke antihypertensive therapy (COSSACS, ENOS) or lower BP in acute stroke (ENOS, SCAST) or haemorrhage (INTERACT 2).

Pneumococcal meningitis secondary to intra-sphenoidal encephalocoele.

Basal encephalocoeles are rare congenital abnormalities of the skull base. The authors describe a rare case of spontaneous CSF leak and meningitis secondary to an intra-sphenoidal encephalocoele. Initial endoscopic transsphenoidal repair was unsuccessful, necessitating a combined subtemporal and transsphenoidal approach to close the defect.

Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis.

AIMS: Randomized controlled trials (RCTs) have shown that the risk of stroke and venous thromboembolism (VTE) is increased with hormone replacement therapy (HRT); the effect on coronary heart disease (CHD) remains unclear. METHODS AND RESULTS: RCTs of HRT were identified. Event rates for cerebrovascular disease [stroke, TIA (transient ischaemic attack)], CHD (myocardial infarction, unstable angina, sudden cardiac death), and VTE (pulmonary embolism, deep vein thrombosis) were analysed. Sensitivity analyses were performed by type of HRT (mono vs. dual) and subject age. 31 trials (44 113 subjects) were identified. HRT was associated with increases in stroke (odds ratio, OR, 1.32, 95% confidence intervals, CI, 1.14-1.53) and VTE (OR 2.05, 95% CI 1.44-2.92). In contrast, CHD events were not increased (OR 1.02, 95% CI 0.90-1.11). Ordinal analyses confirmed that stroke severity was increased with HRT (OR 1.31, 95% CI 1.12-1.54). Although most trials included older subjects, age did not significantly affect risk. The addition of progesterone to oestrogen doubled the risk of VTE. CONCLUSION: HRT is associated with an increased risk of stroke, stroke severity, and VTE, but not of CHD events. Although most trials studied older patients, increased risk was not related to age. Combined HRT increases the risk of VTE compared with oestrogen monotherapy.

It is safe to use transdermal glyceryl trinitrate to lower blood pressure in patients with acute ischaemic stroke with carotid stenosis.

Background: There is concern that blood pressure (BP) lowering in acute stroke may compromise cerebral perfusion and worsen outcome in the presence of carotid stenosis. We assessed the effect of glyceryl trinitrate (GTN) in patients with carotid stenosis using data from the Efficacy of Nitric Oxide in Stroke (ENOS) Trial. Methods: ENOS randomised 4011 patients with acute stroke and raised systolic BP (140-220 mm Hg) to transdermal GTN or no GTN within 48 hours of onset. Those on prestroke antihypertensives were also randomised to stop or continue their medication for 7 days. The primary outcome was the modified Rankin Scale (mRS) at day 90. Ipsilateral carotid stenosis was split: <30%; 30-<50%; 50-<70%; ≥70%. Data are ORs with 95% CIs adjusted for baseline prognostic factors. Results: 2023 (60.5%) ischaemic stroke participants had carotid imaging. As compared with <30%, ≥70% ipsilateral stenosis was associated with an unfavourable shift in mRS (worse outcome) at 90 days (OR 1.88, 95% CI 1.44 to 2.44, p<0.001). Those with ≥70% stenosis who received GTN versus no GTN had a favourable shift in mRS (OR 0.56, 95% CI 0.34 to 0.93, p=0.024). In those with 50-<70% stenosis, continuing versus stopping prestroke antihypertensives was associated with worse disability, mood, quality of life and cognition at 90 days. Clinical outcomes did not differ across bilateral stenosis groups. Conclusions: Following ischaemic stroke, severe ipsilateral carotid stenosis is associated with worse functional outcome at 90 days. GTN appears safe in ipsilateral or bilateral carotid stenosis, and might improve outcome in severe ipsilateral carotid stenosis.

Effect of antihypertensive agents on cerebral blood flow and flow velocity in acute ischaemic stroke: systematic review of controlled studies.

OBJECTIVE: High blood pressure is common in acute stroke and is associated independently with poor outcome. Lowering blood pressure might improve outcome, provided it does not reduce cerebral blood flow in the presence of dysfunctional cerebral autoregulation. METHODS: We performed a systematic review of clinical controlled trials that administered antihypertensive agents within 7 days of ischaemic stroke and measured cerebral blood flow or cerebral blood flow velocity. RESULTS: From 74 identified publications, 11 trials met the criteria. A variety of antihypertensive agents were used: angiotensin-converting enzyme inhibitors (three trials), angiotensin-receptor antagonists (one), calcium antagonists (five), diuretics (one) and nitrates (two). The trials' median quality score was 2.5/5, and the studies used single photon emission computed tomography (five trials), xenon-computed tomography (three) and positron emission tomography (one) for determining cerebral blood flow, and transcranial Doppler (six) for measuring flow velocity. Analysis of randomized controlled trials revealed no alteration in cerebral blood flow for any antihypertensive agent. Nonrandomized trials that assessed blood flow before and after administration of the agents showed an increase in blood flow for calcium channel blockers (standardized mean difference 0.43, 95% confidence interval 0.01-0.85). CONCLUSION: There are few quality studies assessing the effect of antihypertensive agents on cerebral blood flow and flow velocity, and variability in reporting make meta-analysis difficult. However, there is little existing evidence that antihypertensive agents reduce cerebral blood flow in spite of their effects on lowering blood pressure.

Men with epilepsy--the lost tribe? Results of a nationwide survey of men with epilepsy living in the UK.

The incidence of epilepsy is the same in men and women yet more time and energy has been expended on "women's issues" in recent times. In 2004, Epilepsy Action (The British Epilepsy Association) conducted a nationwide survey of men with epilepsy (MWE), who had contacted their helpline in the previous year. The men were comfortable discussing their epilepsy and confident in asking for information. They felt keenly the lack of driving privileges and the type of work available to them. A majority felt the condition adversely affected their self-esteem and quality of life. Most men expressed satisfaction with the quality of care and information they got from their general practitioners and their neurologist.

Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the "Rapid Intervention with GTN in Hypertensive Stroke Trial" (RIGHT, ISRCTN66434824).

Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.

Is lowering blood pressure hazardous in patients with significant ipsilateral carotid stenosis and acute ischaemic stroke? Interim assessment in the 'Efficacy of Nitric Oxide in Stroke' trial.

BACKGROUND: High blood pressure (BP) in acute stroke patients is both common and associated with a poor outcome, although best management remains unclear. Particular uncertainty exists in patients with carotid stenosis in whom lowering BP might reduce cerebral perfusion and worsen outcome. METHODS: Efficacy of Nitric Oxide in Stroke (ENOS) is an international, randomized controlled trial investigating the effect of lowering BP with glyceryl trinitrate in 5000 patients with acute stroke. This analysis is based on patients with ischaemic stroke for whom information on the carotid status was available. Neurological impairment (Scandinavian Stroke Scale) and rate of recurrent stroke were assessed on day 7, and the functional outcome (modified Rankin score) was determined on day 90. ENOS is ongoing, therefore analyses are blinded to treatment. RESULTS: At the time of analysis, 565 patients with ischaemic stroke had been randomized into ENOS and data on carotid status were available in 394 (70%) of these patients. Ipsilateral stenosis > or =50% was present in 50 patients (13%). Six of 344 (2%, 95% confidence interval: 0.7, 4%) patients with ipsilateral stenosis <50% had a recurrent stroke by 7 days as compared with none of 50 patients (0%, 95% confidence interval: 0, 9%) (P=0.73) with stenosis > or =50%. No significant difference in impairment was present on day 7; mean Scandinavian Stroke Scale with stenosis 38.3 versus no stenosis 43.2 (P=0.48). Adjusted functional outcome after 90 days was worse in those with a baseline carotid stenosis > or =50%; median modified Rankin score 3.0 versus 2.0 (P=0.03). CONCLUSION: Interim data provide reassurance that it is reasonable to continue including patients with carotid stenosis into trials of acute BP lowering (such as ENOS).

A randomised controlled trial of triple antiplatelet therapy (aspirin, clopidogrel and dipyridamole) in the secondary prevention of stroke: safety, tolerability and feasibility.

BACKGROUND: Aspirin, dipyridamole and clopidogrel are effective in secondary vascular prevention. Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment in the secondary prevention of ischaemic stroke. METHODOLOGY/PRINCIPAL FINDINGS: A randomised, parallel group, observer-blinded phase II trial compared the combination of aspirin, clopidogrel and dipyridamole with aspirin alone. Adult patients with ischaemic stroke or transient ischaemic attack (TIA) within 5 years were included. The primary outcome was tolerability to treatment assessed as the number of patients completing randomised treatment. Recruitment was halted prematurely after publication of the ESPRIT trial (which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone). 17 patients were enrolled: male 12 (71%), mean age 62 (SD 13) years, lacunar stroke syndrome 12 (71%), median stroke/TIA onset to randomisation 8 months. Treatment was discontinued in 4 of 9 (44%) patients receiving triple therapy vs. none of 8 taking aspirin (p = 0.08). One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications. The number of patients with adverse events and bleeding complications, and their severity, were significantly greater in the triple therapy group (p<0.01). CONCLUSIONS/SIGNIFICANCE: Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates, and their severity, and a trend to increased discontinuations. However, the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN83673558.