Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

Xanthine oxidase inhibition and white matter hyperintensity progression following ischaemic stroke and transient ischaemic attack (XILO-FIST): a multicentre, double-blinded, randomised, placebo-controlled trial.

Background: People who experience an ischaemic stroke are at risk of recurrent vascular events, progression of cerebrovascular disease, and cognitive decline. We assessed whether allopurinol, a xanthine oxidase inhibitor, reduced white matter hyperintensity (WMH) progression and blood pressure (BP) following ischaemic stroke or transient ischaemic attack (TIA). Methods: In this multicentre, prospective, randomised, double-blinded, placebo-controlled trial conducted in 22 stroke units in the United Kingdom, we randomly assigned participants within 30-days of ischaemic stroke or TIA to receive oral allopurinol 300 mg twice daily or placebo for 104 weeks. All participants had brain MRI performed at baseline and week 104 and ambulatory blood pressure monitoring at baseline, week 4 and week 104. The primary outcome was the WMH Rotterdam Progression Score (RPS) at week 104. Analyses were by intention to treat. Participants who received at least one dose of allopurinol or placebo were included in the safety analysis. This trial is registered with ClinicalTrials.gov, NCT02122718. Findings: Between 25th May 2015 and the 29th November 2018, 464 participants were enrolled (232 per group). A total of 372 (189 with placebo and 183 with allopurinol) attended for week 104 MRI and were included in analysis of the primary outcome. The RPS at week 104 was 1.3 (SD 1.8) with allopurinol and 1.5 (SD 1.9) with placebo (between group difference -0.17, 95% CI -0.52 to 0.17, p = 0.33). Serious adverse events were reported in 73 (32%) participants with allopurinol and in 64 (28%) with placebo. There was one potentially treatment related death in the allopurinol group. Interpretation: Allopurinol use did not reduce WMH progression in people with recent ischaemic stroke or TIA and is unlikely to reduce the risk of stroke in unselected people. Funding: The British Heart Foundation and the UK Stroke Association.

Efficacy of erenumab and factors predicting response after 3 months in treatment resistant chronic migraine: a clinical service evaluation.

BACKGROUND: Calcitonin gene-related peptide (CGRP) inhibitors have been developed as options for treatment of chronic and episodic migraine. We present our experience of the use of erenumab in a tertiary headache centre. METHODS: This was a prospective clinical audit of all patients commenced on erenumab following a locally agreed pathway and criteria over a consecutive period. Patients received monthly erenumab 140 mg for 3 months. Data were collected prospectively at baseline and 3 months follow up. RESULTS: One hundred three patients were commenced on erenumab during the study period. Patients had tried a median of 7 previous prophylactics, including onabotulinum toxin A in 94%. At 3 months there was a reduction in median total (28 to 20, 29% reduction, p < 0.0001) and severe (15 to 5, 67% reduction, p < 0.0001) headache days. 39.8% of patients achieved at least a 30% reduction in total headache days; 61.8% of patients achieved at least a 50% reduction in severe headache days. Meeting either of these thresholds was considered a positive response, 68% of patients achieved this. Presence of daily headache pattern was negatively associated with response, (56% response vs. 90% without daily headache, p = 0.0003). There was no association between age, gender, presence of medication overuse or number of previously tried prophylactic treatments and response to erenumab. 43% of patients reported at least one adverse effect, most commonly constipation (26%); treatment was discontinued in 3 patients due to adverse effects. CONCLUSIONS: Erenumab was an effective treatment for chronic migraine in this treatment resistant population over 3 months of follow up. Presence of daily headache predicted poorer response but there was still a significant positive response rate in this group.

Chronic Migraine: An Update on Diagnosis and Management.

BACKGROUND: Chronic migraine is an under-recognized and under-treated disorder. A greater understanding of the pathophysiology of migraine and transformation to chronic migraine has led to the first targeted treatments for chronic migraine. In this review, we review current approaches to the diagnosis and management of chronic migraine and discuss recent and emerging novel therapies. OBJECTIVE: The aim of this study was to provide an update on the diagnosis and management of chronic migraine. METHODS AND MATERIAL: The PubMed database was searched for relevant articles published on or before October 2020. RESULTS AND CONCLUSIONS: Chronic migraine is an under-recognized and under-treated disorder. Prompt diagnosis and appropriate management can lead to a significant improvement in the quality of life with subsequent socioeconomic benefits.

Xanthine oxidase inhibition for the improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) - Protocol for a randomised double blind placebo-controlled clinical trial.

BACKGROUND: Allopurinol, a xanthine oxidase inhibitor, reduced progression of carotid-intima media thickness and lowered blood pressure in a small clinical trial in people with ischaemic stroke. Xanthine oxidase inhibition for improvement of long-term outcomes following ischaemic stroke and transient ischaemic attack (XILO-FIST) aims to assess the effect of allopurinol treatment on white matter hyperintensity progression and blood pressure after stroke. This paper describes the XILO-FIST protocol. METHODS: XILO-FIST is a multicentre randomised double-blind, placebo-controlled, parallel group clinical trial funded by the British Heart Foundation and the Stroke Association. The trial has been adopted by the Scottish Stroke Research Network and the UK Clinical Research Network. The trial is registered in clinicaltrials.gov (registration number NCT02122718). XILO-FIST will randomise 464 participants, aged greater than 50 years, with ischaemic stroke within the past month, on a 1:1 basis, to two years treatment with allopurinol 300 mg twice daily or placebo. Participants will undergo brain magnetic resonance imaging, cognitive assessment, ambulatory blood pressure monitoring and blood sampling at baseline and after two years treatment. The primary outcome will be white matter hyperintensity progression, measured using the Rotterdam progression scale. Secondary outcomes will include change in white matter hyperintensity volume, mean day-time systolic blood pressure and measures of cognitive function. Up to 100 will undergo additional cardiac magnetic resonance imaging in a sub-study of left ventricular mass. DISCUSSION: If white matter hyperintensity progression is reduced, allopurinol could be an effective preventative treatment for patients with ischaemic stroke and clinical endpoint studies would be needed. If allopurinol reduces blood pressure after stroke, then it could be used to help patients reach blood pressure targets.

Vasoreactivity in CADASIL: Comparison to structural MRI and neuropsychology.

Impaired cerebrovascular reactivity precedes histological and clinical evidence of CADASIL in animal models. We aimed to more fully characterise peripheral and cerebral vascular function and reactivity in a cohort of adult CADASIL patients, and explore the associations of these with conventional clinical, imaging and neuropsychological measures. A total of 22 adults with CADASIL gave informed consent to participate in an exploratory study of vascular function in CADASIL. Clinical assessment, comprehensive vascular assessment, MRI and neuropsychological testing were conducted. We measured cerebral vasoreactivity with transcranial Doppler and arterial spin labelling MRI with hypercapnia challenge. Number and volume of lacunes, subcortical hyperintensity volume, microbleeds and normalised brain volume were assessed on MRI. Analysis was exploratory and examined the associations between different markers. Cerebrovascular reactivity measured by ASL correlated with peripheral vasoreactivity measured by flow mediated dilatation. Subjects with ≥5 lacunes were older, with higher carotid intima-media thickness and had impaired cerebral and peripheral vasoreactivity. Subjects with depressive symptoms, disability or delayed processing speed also showed a trend to impaired vasoreactivity. Impaired vasoreactivity and vascular dysfunction may play a significant role in the pathophysiology of CADASIL, and vascular assessments may be useful biomarkers of severity in both longitudinal and clinical trials.

Oxygen challenge magnetic resonance imaging in healthy human volunteers.

Oxygen challenge imaging involves transient hyperoxia applied during deoxyhaemoglobin sensitive (T2*-weighted) magnetic resonance imaging and has the potential to detect changes in brain oxygen extraction. In order to develop optimal practical protocols for oxygen challenge imaging, we investigated the influence of oxygen concentration, cerebral blood flow change, pattern of oxygen administration and field strength on T2*-weighted signal. Eight healthy volunteers underwent multi-parametric magnetic resonance imaging including oxygen challenge imaging and arterial spin labelling using two oxygen concentrations (target FiO2 of 100 and 60%) administered consecutively (two-stage challenge) at both 1.5T and 3T. There was a greater signal increase in grey matter compared to white matter during oxygen challenge (p < 0.002 at 3T, P < 0.0001 at 1.5T) and at FiO2 = 100% compared to FiO2 = 60% in grey matter at both field strengths (p < 0.02) and in white matter at 3T only (p = 0.0314). Differences in the magnitude of signal change between 1.5T and 3T did not reach statistical significance. Reduction of T2*-weighted signal to below baseline, after hyperoxia withdrawal, confounded interpretation of two-stage oxygen challenge imaging. Reductions in cerebral blood flow did not obscure the T2*-weighted signal increases. In conclusion, the optimal protocol for further study should utilise target FiO2 = 100% during a single oxygen challenge. Imaging at both 1.5T and 3T is clinically feasible.

Respiratory challenge MRI: Practical aspects.

Respiratory challenge MRI is the modification of arterial oxygen (PaO2) and/or carbon dioxide (PaCO2) concentration to induce a change in cerebral function or metabolism which is then measured by MRI. Alterations in arterial gas concentrations can lead to profound changes in cerebral haemodynamics which can be studied using a variety of MRI sequences. Whilst such experiments may provide a wealth of information, conducting them can be complex and challenging. In this paper we review the rationale for respiratory challenge MRI including the effects of oxygen and carbon dioxide on the cerebral circulation. We also discuss the planning, equipment, monitoring and techniques that have been used to undertake these experiments. We finally propose some recommendations in this evolving area for conducting these experiments to enhance data quality and comparison between techniques.

Structural remodeling of white matter in the contralesional hemisphere is correlated with early motor recovery in patients with subcortical infarction.

PURPOSE: This study aimed to identify brain areas with white matter changes that contribute to motor recovery of affected limbs during acute to sub-acute phases of subcortical infarction. METHODS: Diffusion tensor imaging was performed 1, 4, and 12 weeks after stroke onset in 18 patients with acute subcortical infarct, and in 18 age- and risk factor-matched controls. Fugl-Meyer scale was used to assess levels of motor impairment, and Statistical Parametric Mapping was applied to determine fractional anisotropy (FA) changes for the entire brain in order to identify areas correlated with motor recovery. RESULTS: Fugl-Meyer scores of patients at 4 and 12 weeks were significantly higher than those at 1 week (all p < 0.01). Accompanying with the progressive decreases of FA in the corticospinal tract above and below the stroke lesion, progressive increases of FA in the contralesional medial frontal gyrus, and thalamocortical connections including projections to the somatosensory cortices, primary motor cortex, and premotor areas, were positively correlated with Fugl-Meyer scores (all p < 0.005) within 12 weeks following acute subcortical infarction. CONCLUSIONS: Remodeling of white matter in contralesional brain regions related to motor, cognition, and sensory processing may facilitate early motor recovery in patients with an acute infarct.

Detection of ischemic penumbra using combined perfusion and T2* oxygen challenge imaging.

BACKGROUND: Acute ischemic stroke is common and disabling, but there remains a paucity of acute treatment options and available treatment (thrombolysis) is underutilized. Advanced brain imaging, designed to identify viable hypoperfused tissue (penumbra), could target treatment to a wider population. Existing magnetic resonance imaging and computed tomography-based technologies are not widely used pending validation in ongoing clinical trials. T2* oxygen challenge magnetic resonance imaging, by providing a more direct readout of tissue viability, has the potential to identify more patients likely to benefit from thrombolysis - irrespective of time from stroke onset - and patients within and beyond the 4·5 h thrombolysis treatment window who are unlikely to benefit and are at an increased risk of hemorrhage. AIMS: This study employs serial multimodal imaging and voxel-based analysis to develop optimal data processing for T2* oxygen challenge penumbra assessment. Tissue in the ischemic hemisphere is compartmentalized into penumbra, ischemic core, or normal using T2* oxygen challenge (single threshold) or T2* oxygen challenge plus cerebral blood flow (dual threshold) data. Penumbra defined by perfusion imaging/apparent diffusion coefficient mismatch (dual threshold) is included for comparison. METHODS: Permanent middle cerebral artery occlusion was induced in male Sprague-Dawley rats (n = 6) prior to serial multimodal imaging: T2* oxygen challenge, diffusion-weighted and perfusion imaging (cerebral blood flow using arterial spin labeling). RESULTS: Across the different methods evaluated, T2* oxygen challenge combined with perfusion imaging most closely predicted 24 h infarct volume. Penumbra volume declined from one to four-hours post-stroke: mean ± SD, 77 ± 44 to 49 ± 37 mm(3) (single T2* oxygen challenge-based threshold); 55 ± 41 to 37 ± 12 mm(3) (dual T2* oxygen challenge/cerebral blood flow); 84 ± 64 to 42 ± 18 mm(3) (dual cerebral blood flow/apparent diffusion coefficient), as ischemic core grew: 155 ± 37 to 211 ± 36 mm(3) (single apparent diffusion coefficient threshold); 178 ± 56 to 205 ± 33 mm(3) (dual T2* oxygen challenge/cerebral blood flow); 139 ± 30 to 168 ± 38 mm(3) (dual cerebral blood flow/apparent diffusion coefficient). There was evidence of further lesion growth beyond four-hours (T2-defined edema-corrected infarct, 231 ± 19 mm(3) ). CONCLUSIONS: In conclusion, T2* oxygen challenge combined with perfusion imaging has advantages over alternative magnetic resonance imaging techniques for penumbra detection by providing serial assessment of available penumbra based on tissue viability.

Derivation and evaluation of thresholds for core and tissue at risk of infarction using CT perfusion.

BACKGROUND AND PURPOSE: Computed tomography perfusion provides information on tissue viability according to proposed thresholds. We evaluated thresholds for ischemic core and tissue at risk and subsequently tested their accuracy in independent datasets. MATERIALS AND METHODS: Tissue at risk was evaluated in patients with persistent arterial occlusions, and ischemic core thresholds in patients with recanalization and major clinical improvement. Scans were randomly allocated to derivation or validation groups for tissue at risk and core analysis. Optimum thresholds using mean transit time (MTT), cerebral blood flow (CBF), cerebral blood volume, and delay time (DT) were assessed. RESULTS: Absolute MTT, relative MTT and DT were best derived predictors of tissue at risk with thresholds of ≥ 7 seconds, ≥ 125%, and ≥ 2 seconds respectively. DT ≥ 2 seconds was the best predictor in the validation dataset (95% agreement levels = -44 to +30 mL, Bias = -6.9). Absolute and relative MTT were the best derived predictors of infarct volume in the core group (8 seconds and 125% respectively) but relative CBF of ≤ 45% performed best in the core validation dataset. CONCLUSIONS: Time-based perfusion thresholds perform well as predictors of tissue at risk of infarction with DT the best predictor. Relative CBF was the best predictor of ischemic core. Evaluation in larger populations is needed to confirm the performance of tissue viability thresholds.

Clinical relevance and practical implications of trials of perfusion and angiographic imaging in patients with acute ischaemic stroke: a multicentre cohort imaging study.

BACKGROUND: In randomised trials testing treatments for acute ischaemic stroke, imaging markers of tissue reperfusion and arterial recanalisation may provide early response indicators. OBJECTIVE: To determine the predictive value of structural, perfusion and angiographic imaging for early and late clinical outcomes and assess practicalities in three comprehensive stroke centres. METHODS: We recruited patients with potentially disabling stroke in three stroke centres, performed magnetic resonance (MR) or CT, including perfusion and angiography imaging, within 6 h, at 72 h and 1 month after stroke. We assessed the National Institutes of Health Stroke Scale (NIHSS) score serially and functional outcome at 3 months, tested associations between clinical variables and structural imaging, several perfusion parameters and angiography. RESULTS: Among 83 patients, median age 71 (maximum 89), median NIHSS 7 (range 1-30), 38 (46%) received alteplase, 41 (49%) had died or were dependent at 3 months. Most baseline imaging was CT (76%); follow-up was MR (79%) despite both being available acutely. At presentation, perfusion lesion size varied considerably between parameters (p<0.0001); 40 (48%) had arterial occlusion. Arterial occlusion and baseline perfusion lesion extent were both associated with baseline NIHSS (p<0.0001). Recanalisation by 72 h was associated with 1 month NIHSS (p=0.0007) and 3 month functional outcome (p=0.048), whereas tissue reperfusion, using even the best perfusion parameter, was not (p=0.11, p=0.08, respectively). CONCLUSION: Early recanalisation on angiography appeared to predict clinical outcome more directly than did tissue reperfusion. Acute assessment with CT and follow-up with MR was practical and feasible, did not preclude image analysis, and would enhance trial recruitment and generalisability of results.

Multi-center prediction of hemorrhagic transformation in acute ischemic stroke using permeability imaging features.

Permeability images derived from magnetic resonance (MR) perfusion images are sensitive to blood-brain barrier derangement of the brain tissue and have been shown to correlate with subsequent development of hemorrhagic transformation (HT) in acute ischemic stroke. This paper presents a multi-center retrospective study that evaluates the predictive power in terms of HT of six permeability MRI measures including contrast slope (CS), final contrast (FC), maximum peak bolus concentration (MPB), peak bolus area (PB), relative recirculation (rR), and percentage recovery (%R). Dynamic T2*-weighted perfusion MR images were collected from 263 acute ischemic stroke patients from four medical centers. An essential aspect of this study is to exploit a classifier-based framework to automatically identify predictive patterns in the overall intensity distribution of the permeability maps. The model is based on normalized intensity histograms that are used as input features to the predictive model. Linear and nonlinear predictive models are evaluated using a cross-validation to measure generalization power on new patients and a comparative analysis is provided for the different types of parameters. Results demonstrate that perfusion imaging in acute ischemic stroke can predict HT with an average accuracy of more than 85% using a predictive model based on a nonlinear regression model. Results also indicate that the permeability feature based on the percentage of recovery performs significantly better than the other features. This novel model may be used to refine treatment decisions in acute stroke.

Rare neurological diseases: a practical approach to management.

Although neurologists are frequently faced with the management of rare diseases, there is little generic guidance for the approach to management. There are complexities with respect to diagnosis, counselling, treatment and monitoring which are idiosyncratic to rare diseases. Here we use a case report as the basis for discussion of the management of rare neurological diseases. We discuss current issues, guidance from regulatory bodies, and offer practical tips for diagnosis, treatment and monitoring, including the use of decision tree analysis. We offer a generic algorithm to aid neurologists when facing rare conditions.

Crossed cerebellar diaschisis: insights into oxygen challenge MRI.

Hyperoxia during T2*-weighted magnetic resonance imaging (oxygen challenge imaging (OCI)) causes T2*-weighted signal change that is dependent on cerebral blood volume (CBV) and oxygen extraction fraction (OEF). Crossed cerebellar diaschisis (CCD), where CBV is reduced but OEF is maintained, may be used to understand the relative contributions of OEF and CBV to OCI results. In subjects with large hemispheric strokes, OCI showed reduced signal change in the contralesional cerebellum (P=0.027, n=12). This was associated with reduced CBV in contralesional cerebellum (P=0.039, n=9). CCD may be a useful model to determine the relative contribution of CBV to signal change measured by OCI.

Multivoxel MR spectroscopy in acute ischemic stroke: comparison to the stroke protocol MRI.

BACKGROUND AND PURPOSE: Few patients with stroke have been imaged with MR spectroscopy (MRS) within the first few hours after onset. We compared data from current MRI protocols to MRS in subjects with ischemic stroke. METHODS: MRS was incorporated into the standard clinical MRI stroke protocol for subjects <24 hours after onset. MRI and clinical correlates for the metabolic data from MRS were sought. RESULTS: One hundred thirty-six MRS voxels from 32 subjects were analyzed. Lactate preceded the appearance of the lesion on diffusion-weighted imaging in some voxels but in others lagged behind it. Current protocols may predict up to 41% of the variance of MRS metabolites. Serum glucose concentration and time to maximum partially predicted the concentration of all major metabolites. CONCLUSIONS: MRS may be helpful in acute stroke, especially for lactate detection when perfusion-weighted imaging is unavailable. Current MRI protocols do provide surrogate markers for some indices of metabolic activity.

Pilot results of in vivo brain glutathione measurements in stroke patients.

Measurement of glutathione concentration for the study of redox status in subjects with neurological disease has been limited to peripheral markers. We recruited 19 subjects with large strokes. Using magnetic resonance spectroscopy we measured brain glutathione concentration in the stroke region and in healthy tissue to calculate a glutathione-ratio. Elevated glutathione-ratio was observed in subacute (<72 hours) subjects without hemorrhagic transformation (mean=1.19, P=0.03, n=6). No trend was seen when all subjects were considered (n=19, 3 to 754 hours, range=0.45 to 1.41). This technique can detect glutathione changes because of disease, and may be valuable in clinical trials of stroke and other neurological diseases.

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: an important cause of stroke in young people.

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes is a progressive, multisystem mitochondrial disease affecting children and young adults. Patients acquire disability through stroke-like episodes and have an increased mortality. Eighty per cent of cases have the mitochondrial mutation m.3243A>G which is linked to respiratory transport chain dysfunction and oxidative stress in energy demanding organs, particularly muscle and brain. It typically presents with seizures, headaches and acute neurological deficits mimicking stroke. It is an important differential in patients presenting with stroke, seizures, or suspected central nervous system infection or vasculitis. Investigations should exclude other aetiologies and include neuroimaging and cerebrospinal fluid analysis. Mutation analysis can be performed on urine samples. There is no high quality evidence to support the use of any of the agents reported in small studies. This article summarises the core clinical, biochemical, radiological and genetic features and discusses the evidence for a number of potential therapies.