Circadian and Diurnal Regulation of Cerebral Blood Flow.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.

BACKGROUND: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown. METHODS: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO2 on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q. RESULTS: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; P=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P<0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P=0.007), CVR-WMH (0.07, 0-0.14; P=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P=4.9×10-8; cilostazol-placebo, 0.06, 0.03-0.09; P=5.1×10-5). Both drugs increased headaches (P=1.1×10-4), while cilostazol increased moderate-severe diarrhea (P=0.013). CONCLUSIONS: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease. REGISTRATION: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

Low Heart Rate Is Associated with Cerebral Pulsatility after TIA or Minor Stroke.

OBJECTIVE: Beta-blockers are beneficial in coronary artery disease but less so in stroke prevention and dementia, potentially due to reduced heart rate (HR). Cerebral pulsatility is strongly associated with cerebral small vessel disease (SVD) and may be increased by lower diastolic pressures resulting from longer cardiac cycles. METHODS: Patients 4-6 weeks after TIA or non-disabling stroke (Oxford Vascular Study) underwent 5 minutes continuous monitoring of blood pressure (BP), electrocardiogram (ECG), and middle cerebral artery flow velocity (transcranial ultrasound). Beat-to-beat relationships between HR, blood pressure and Gosling's pulsatility index (MCA-PI) are reported as beta-coefficients from general linear models for each individual. RESULTS: Across 759 patients, average MCA-PI during monitoring was associated with lower HR and diastolic BP (DBP) and greater systolic BP (SBP) (∆MCA-PI per 10 bpm/mmHg: -0.02, -0.04, 0.03, all p < 0.001), with HR particularly associated with low end-diastolic cerebral velocity (0.86, p = 0.014). Beat-to-beat HR was strongly associated with concurrent low DBP and high SBP, potentially mediating the association with greater beat-to-beat cerebral pulsatility (average ∆MCA-PI vs HR/DBP/SBP unadjusted: -0.062, -0.052, 0.0092; adjusted for concurrent BP: -0.039, -0.11, 0.041). The beat-to-beat association between HR and MCA-PI increased with age, beta-blockers, arterial stiffness, low HR (age > 70 + HR < 65 vs age < 70 + HR > 65: -0.081 vs -0.024, interaction p < 0.001), and severe SVD on MRI (age > 70 + severe vs age < 70 + none: -0.087 vs -0.047, interaction p = 0.03), with interactions between age, severe SVD, and low HR synergistically increasing MCA-PI. INTERPRETATION: Low HR is associated with greater cerebral pulsatility in patients with SVD, potentially mediated by lower diastolic blood flow and representing a novel potential treatment target. ANN NEUROL 2022;92:909-920.

Consistencies and Differences in Intermediate Physiological Phenotypes of Vascular Ageing between Ischaemic Stroke Aetiologies.

OBJECTIVE: Arterial stiffness, cerebral pulsatility, and beat-to-beat blood pressure variability partly mediate the relationship between hypertension and stroke, but it is unknown if these intermediate phenotypes of vascular ageing differ between stroke aetiologies. We therefore aimed to characterize differences in these intermediate cardiovascular phenotypes between patients presenting with strokes of different aetiologies. METHODS: In consecutive patients on best medical management 1 month after TIA or nondisabling stroke (Oxford Vascular Study), arterial stiffness (PWV) was measured by applanation tonometry (Sphygmocor), middle cerebral blood flow velocity, and pulsatility index (MCA-PI) were measured by transcranial ultrasound (TCD, DWL Doppler Box), and beat-to-beat BP variability was measured with a Finometer. Differences between patients with large artery (LAS), small vessel (SVD), cardioembolic (CE), or undetermined events were derived, including adjustment for cardiovascular risk factors. Relationships were characterized by mixed linear models. RESULTS: In 909 eligible patients, MCA-PI, PWV, and SBPV were all positively skewed. Mean values were greatest in LAS than CE and lowest in SVD (p < 0.001). However, after adjustment for age, sex, and risk factors, PI was greatest in LAS and lowest in CE stroke, whilst PWV was greatest in SVD and undetermined stroke (p < 0.001). In multivariate linear models, age was more strongly associated with PWV and PI in patients with small vessel stroke than other aetiologies, particularly under the age of 65, but SBPV was only weakly associated with demographic indices in all stroke subtypes. CONCLUSIONS: Intermediate cardiovascular phenotypes of vascular ageing had similar demographic associations between stroke aetiologies, but these were particularly strong in patients with small vessel stroke under the age of 65, implying a potential role of these phenotypes in increasing stroke risk in this patient group.

New Insights Into Cerebrovascular Pathophysiology and Hypertension.

Despite advances in acute management and prevention of cerebrovascular disease, stroke and vascular cognitive impairment together remain the world's leading cause of death and neurological disability. Hypertension and its consequences are associated with over 50% of ischemic and 70% of hemorrhagic strokes but despite good control of blood pressure (BP), there remains a 10% risk of recurrent cerebrovascular events, and there is no proven strategy to prevent vascular cognitive impairment. Hypertension evolves over the lifespan, from predominant sympathetically driven hypertension with elevated mean BP in early and mid-life to a late-life phenotype of increasing systolic and falling diastolic pressures, associated with increased arterial stiffness and aortic pulsatility. This pattern may partially explain both the increasing incidence of stroke in younger adults as well as late-onset, chronic cerebrovascular injury associated with concurrent systolic hypertension and historic mid-life diastolic hypertension. With increasing arterial stiffness and autonomic dysfunction, BP variability increases, independently predicting the risk of ischemic and intracerebral hemorrhage, and is potentially modifiable beyond control of mean BP. However, the interaction between hypertension and control of cerebral blood flow remains poorly understood. Cerebral small vessel disease is associated with increased pulsatility in large cerebral vessels and reduced reactivity to carbon dioxide, both of which are being targeted in early phase clinical trials. Cerebral arterial pulsatility is mainly dependent upon increased transmission of aortic pulsatility via stiff vessels to the brain, while cerebrovascular reactivity reflects endothelial dysfunction. In contrast, although cerebral autoregulation is critical to adapt cerebral tone to BP fluctuations to maintain cerebral blood flow, its role as a modifiable risk factor for cerebrovascular disease is uncertain. New insights into hypertension-associated cerebrovascular pathophysiology may provide key targets to prevent chronic cerebrovascular disease, acute events, and vascular cognitive impairment.

Aortic Stiffness, Pulse Pressure, and Cerebral Pulsatility Progress Despite Best Medical Management: The OXVASC Cohort.

BACKGROUND: Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. METHODS: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P<0.0001) and aoPP (3.5%; P<0.0001) but not significantly for MCA-PI overall (0.93; P=0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P<0.0001), while aoPP and MCA-PI increased significantly above the age of 55 years (aoPP, P<0.0001; MCA-PI, P=0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP (P<0.001). CONCLUSIONS: Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study.

BACKGROUND: A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes. METHODS: For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 µg/L. We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3-6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. FINDINGS: Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32-55) was lower than in the non-VITT group (57 years; 41-62; p=0·0045). Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2-4) than non-VITT patients (two, 2-3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022). INTERPRETATION: Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate. FUNDING: None.

Midlife blood pressure is associated with the severity of white matter hyperintensities: analysis of the UK Biobank cohort study.

AIMS: White matter hyperintensities (WMH) progress with age and hypertension, but the key period of exposure to elevated blood pressure (BP), and the relative role of systolic BP (SBP) vs. diastolic BP (DBP), remains unclear. This study aims to determine the relationship between WMH and concurrent vs. past BP. METHODS AND RESULTS: UK Biobank is a prospective community-based cohort of 40-69-year olds from 22 centres, with magnetic resonance imaging in a subgroup of over 40 000 people at 4-12 years after baseline assessment. Standardized associations between WMH load (WMH volume normalized by total white matter volume and logit-transformed) and concurrent vs. past BP were determined using linear models, adjusted for age, sex, cardiovascular risk factors, BP source, assessment centre, and time since baseline. Associations adjusted for regression dilution bias were determined between median WMH and usual SBP or DBP, stratified by age and baseline BP.In 37 041 eligible participants with WMH data and BP measures, WMH were more strongly associated with concurrent SBP [DBP: ß = 0.064, 95% confidence interval (CI) 0.050-0.078; SBP: ß = 0.076, 95% CI 0.062-0.090], but the strongest association was for past DBP (DBP: ß = 0.087, 95% CI 0.064-0.109; SBP: ß = 0.045, 95% CI 0.022-0.069), particularly under the age of 50 (DBP: ß = 0.103, 95% CI 0.055-0.152; SBP: ß = 0.012, 95% CI -0.044 to 0.069). Due to the higher prevalence of elevated SBP, median WMH increased 1.126 (95% CI 1.107-1.146) per 10 mmHg usual SBP and 1.106 (95% CI 1.090-1.122) per 5 mmHg usual DBP, whilst the population attributable fraction of WMH in the top decile was greater for elevated SBP (19.1% for concurrent SBP; 24.4% for past SBP). Any increase in BP, even below 140 for SBP and below 90 mmHg for DBP, and especially if requiring antihypertensive medication, was associated with increased WMH. CONCLUSIONS: WMH were strongly associated with concurrent and past elevated BP with the population burden of severe WMH greatest for SBP. However, before the age of 50, DBP was more strongly associated with WMH. Long-term prevention of WMH may require control of even mildly elevated midlife DBP.

Body Mass Index and Arterial Stiffness Are Associated With Greater Beat-to-Beat Blood Pressure Variability After Transient Ischemic Attack or Minor Stroke.

[Figure: see text].

Confounding of Cerebral Blood Flow Velocity by Blood Pressure During Breath Holding or Hyperventilation in Transient Ischemic Attack or Stroke.

Background and Purpose- Breath holding (BH) and hyperventilation are used to assess abnormal cerebrovascular reactivity, often in relation to severity of small vessel disease and risk of stroke with carotid stenosis, but responses may be confounded by blood pressure (BP) changes. We compared effects of BP and end-tidal carbon dioxide (etCO2) on middle cerebral artery mean flow velocity (MFV) in consecutive transient ischemic attack and minor stroke patients. Methods- In the population-based, prospective OXVASC (Oxford Vascular Study) phenotyped cohort, change in MFV on transcranial Doppler ultrasound (ΔMFV, DWL-DopplerBox), beat-to-beat BP (Finometer), and etCO2 was measured during 30 seconds of BH or hyperventilation. Two blinded reviewers independently assessed recording quality. Dependence of ΔMFV on ΔBP and ΔetCO2 was determined by general linear models, stratified by quartiles. Results- Four hundred eighty-eight of 602 (81%) patients with adequate bone windows had high-quality recordings, more often in younger participants (64.6 versus 68.7 years; P<0.01), whereas 426 had hyperventilation tests (70.7%). During BH, ΔMFV was correlated with a rise in mean blood pressure (MBP; r2=0.15, P<0.001) but not ΔCO2 (r2=0.002, P=0.32), except in patients with ΔMBP <10% (r2=0.13, P<0.001). In contrast during hyperventilation, the fall in MFV was similarly correlated with reduction in CO2 and reduction in MBP (ΔCO2: r2=0.13, P<0.001; ΔMBP: r2=0.12, P<0.001), with a slightly greater effect of ΔCO2 when ΔMBP was <10% (r2=0.15). Stratifying by quartile, MFV increased linearly during BH across quartiles of ΔMBP, with no increase with ΔetCO2. In contrast, during hyperventilation, MFV decreased linearly with ΔetCO2, independent of ΔMBP. Conclusions- In older patients with recent transient ischemic attack or minor stroke, cerebral blood flow responses to BH were confounded by BP changes but reflected etCO2 change during hyperventilation. Correct interpretation of cerebrovascular reactivity responses to etCO2, including in small vessel disease and carotid stenosis, requires concurrent BP measurement.

Two case reports of distal upper limb weakness following influenza-like illness: an emerging pattern of para-infectious myositis in adults.

BACKGROUND: Myositis is a recognised complication of numerous systemic viral infections including influenza. In adults the typical pattern is characterised by myalgia and marked proximal muscle weakness in upper and lower limbs and resolves slowly over weeks rather than days. CASE PRESENTATION: Here, we describe two male patients with myositis with an unusual distribution of weakness in the distal upper limbs, which both followed a flu-like illness and resolved spontaneously. Both patients had moderate elevations in creatine kinase, extensive negative serological investigations, normal nerve conduction studies and myopathic changes on electromyography. CONCLUSIONS: In the para-infectious context, myositis is an important differential of acute distal upper limb weakness. This unusual pattern of acute muscle weakness should be recognised to avoid unnecessary in treatments. Similar cases in the recent literature in male patients between the ages of 25 to 55 are reviewed and suggest an emerging pattern of para-infectious myositis.

Prognostic Significance of Blood Pressure Variability on Beat-to-Beat Monitoring After Transient Ischemic Attack and Stroke.

BACKGROUND AND PURPOSE: Visit-to-visit and day-to-day blood pressure (BP) variability (BPV) predict an increased risk of cardiovascular events but only reflect 1 form of BPV. Beat-to-beat BPV can be rapidly assessed and might also be predictive. METHODS: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (Oxford Vascular Study), BPV (coefficient of variation) was measured beat-to-beat for 5 minutes (Finometer), day-to-day for 1 week on home monitoring (3 readings, 3× daily), and on awake ambulatory BP monitoring. BPV after 1-month standard treatment was related (Cox proportional hazards) to recurrent stroke and cardiovascular events for 2 to 5 years, adjusted for mean systolic BP. RESULTS: Among 520 patients, 26 had inadequate beat-to-beat recordings, and 22 patients were in atrial fibrillation. Four hundred five patients had all forms of monitoring. Beat-to-beat BPV predicted recurrent stroke and cardiovascular events independently of mean systolic BP (hazard ratio per group SD, stroke: 1.47 [1.12-1.91]; P=0.005; cardiovascular events: 1.41 [1.08-1.83]; P=0.01), including after adjustment for age and sex (stroke: 1.47 [1.12-1.92]; P=0.005) and all risk factors (1.40 [1.00-1.94]; P=0.047). Day-to-day BPV was less strongly associated with stroke (adjusted hazard ratio, 1.29 [0.97-1.71]; P=0.08) but similarly with cardiovascular events (1.41 [1.09-1.83]; P=0.009). BPV on awake ambulatory BP monitoring was nonpredictive (stroke: 0.89 [0.59-1.35]; P=0.59; cardiovascular events: 1.08 [0.77-1.52]; P=0.65). Despite a weak correlation (r=0.119; P=0.02), beat-to-beat BPV was associated with risk of recurrent stroke independently of day-to-day BPV (1.41 [1.05-1.90]; P=0.02). CONCLUSIONS: Beat-to-beat BPV predicted recurrent stroke and cardiovascular events, independently of mean systolic BP and risk factors but short-term BPV on ambulatory BP monitoring did not. Beat-to-beat BPV may be a useful additional marker of cardiovascular risk.

Magnetic Resonance Imaging Measurement of Transmission of Arterial Pulsation to the Brain on Propranolol Versus Amlodipine.

BACKGROUND AND PURPOSE: Cerebral arterial pulsatility is associated with leukoaraiosis and depends on central arterial pulsatility and arterial stiffness. The effect of antihypertensive drugs on transmission of central arterial pulsatility to the cerebral circulation is unknown, partly because of limited methods of assessment. METHODS: In a technique-development pilot study, 10 healthy volunteers were randomized to crossover treatment with amlodipine and propranolol. At baseline and on each drug, we assessed aortic (Sphygmocor) and middle cerebral artery pulsatility (TCDtranscranial ultrasound). We also performed whole-brain, 3-tesla multiband blood-oxygen level dependent magnetic resonance imaging (multiband factor 6, repetition time=0.43s), concurrent with a novel method of continuous noninvasive blood pressure monitoring. Drug effects on relationships between cardiac cycle variation in blood pressure and blood-oxygen level dependent imaging were determined (fMRI Expert Analysis Tool, fMRIB Software Library [FEAT-FSL]). RESULTS: Aortic pulsatility was similar on amlodipine (27.3 mm Hg) and propranolol (27.9 mm Hg, P diff=0.33), while MCA pulsatility increased nonsignificantly more from baseline on propranolol (+6%; P=0.09) than amlodipine (+1.5%; P=0.58). On magnetic resonance imaging, cardiac frequency blood pressure variations were found to be significantly more strongly associated with blood-oxygen level dependent imaging on propranolol than amlodipine. CONCLUSIONS: We piloted a novel method of assessment of arterial pulsatility with concurrent high-frequency blood-oxygen level dependent magnetic resonance imaging and noninvasive blood pressure monitoring. This method was able to identify greater transmission of aortic pulsation on propranolol than amlodipine, which warrants further investigation.

Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III.

BACKGROUND AND PURPOSE: The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography-based planimetry (CTP). METHODS: In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. RESULTS: In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r(2)=0.93) than with site-ABC (r(2)=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm(3); CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (κ=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. CONCLUSIONS: ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

Seasonal variation in Guillain-Barré syndrome: a systematic review, meta-analysis and Oxfordshire cohort study.

INTRODUCTION: Evidence for seasonal variation in incidence and subtype of Guillain-Barré syndrome (GBS) is contradictory, but has implications for provision of neurological services and understanding pathogenesis. METHODS: We searched PubMed and EMBASE between inception and January 2014, including all studies reporting seasonal incidence of GBS. We included a retrospective cohort study of patients with GBS at the John Radcliffe Hospital, Oxford 2001-2012 and determined the seasonal variation in GBS incidence and length of stay. The incidence rate ratio (IRR) for winter versus summer was pooled across studies by fixed and random effects meta-analysis weighted by inverse variance, stratified by geographical region, infectious prodrome and GBS subtype. RESULTS: Across 9836 patients from 42 studies there was a 14% increased risk of GBS in winter versus summer (IRR=1.14, 1.02-1.27, p=0.020), with significant heterogeneity between studies (I(2)=77%, p<0.0001), including significant seasonal variation in Oxford (n=140; p=0.037) for winter versus summer (IRR=1.92, 1.18-3.11, p=0.004) but a non-significantly reduced length of stay for winter versus other seasons (15 vs 21 days, p=0.08). Across all studies, there was greater seasonal variation with respiratory prodrome (IRR=3.06, 1.84-5.11, p<0.0001) than diarrhoeal prodrome (IRR=1.10, 0.60-2.00, p=0.76) and a greater incidence in winter in Western countries (IRR=1.28), the Far East (IRR=1.20) and Middle East (IRR=1.12), with a lower incidence in the Indian subcontinent (IRR=0.86) and Latin America (IRR=0.75). DISCUSSION: Incidence of GBS was greater in winter than summer, but this was not evident in all geographical regions. This is likely to be related to regional variation in prodromal illnesses.

Physiological correlates of beat-to-beat, ambulatory, and day-to-day home blood pressure variability after transient ischemic attack or minor stroke.

BACKGROUND AND PURPOSE: Visit-to-visit and day-to-day variability in systolic blood pressure (SBP) are associated with an increased risk of stroke, more strongly than variability on 24-hour ambulatory BP monitoring, but underlying physiological mechanisms are unclear. We related potentially relevant physiological characteristics to beat-to-beat, ambulatory, and day-to-day BP variability to identify underlying mechanisms and potential therapeutic targets. METHODS: BP variability (coefficient of variation [CV]) on 1-month home BP monitoring (3 sitting readings, 3× daily), on 24-hour ambulatory BP monitoring, and on 5-minute beat-to-beat monitoring was related to BP reactivity (to mental arithmetic), arterial aging (aortic stiffness: carotid-femoral pulse wave velocity; aortic pulsatility), heart rate variability (CV of normal-to-normal R-R interval), and orthostatic responses. RESULTS: In 223 patients within 6 weeks of a transient ischemic attack or minor stroke, beat-to-beat and home SBP-CVs were associated with response to arithmetic (beat-to-beat odds ratio per SD=1.64; P<0.0001 and home BP monitoring, 1.41; P=0.025), aortic stiffness (1.84; P<0.0001 and 1.31; P=0.04), aortic pulsatility (1.98; P<0.0001 and 1.61; P<0.0001), and heart rate variability-CV of normal-to-normal R-R interval (1.34; P=0.03 and 1.35; P=0.03), independently of age, sex, and aortic BP. Orthostatic BP changes were associated only with SBP-CV on home BP monitoring (0.62; P=0.002). In contrast, no physiological measures were associated with within-day BP variability on awake ambulatory BP monitoring except response to mental arithmetic (1.40; P=0.01). CONCLUSIONS: Beat-to-beat and day-to-day SBP variability, but not variability on ambulatory BP monitoring, had similar physiological correlates, suggesting common underlying mechanisms and identifying potentially treatable targets that may be responsible for the relationship between SBP variability and stroke risk.

Response of day-to-day home blood pressure variability by antihypertensive drug class after transient ischemic attack or nondisabling stroke.

BACKGROUND AND PURPOSE: Visit-to-visit variability in systolic blood pressure (SBP) is associated with an increased risk of stroke and was reduced in randomized trials by calcium channel blockers and diuretics but not by renin-angiotensin system inhibitors. However, time of day effects could not be determined. Day-to-day variability on home BP readings predicts stroke risk and potentially offers a practical method of monitoring response to variability-directed treatment. METHODS: SBP mean, maximum, and variability (coefficient of variation=SD/mean) were determined in 500 consecutive transient ischemic attack or minor stroke patients on 1-month home BP monitoring (3 BPs, 3× daily). Hypertension was treated to a standard protocol. Differences in SBP variability from 3 to 10 days before to 8 to 15 days after starting or increasing calcium channel blockers/diuretics versus renin-angiotensin system inhibitors versus both were compared by general linear models, adjusted for risk factors and baseline BP. RESULTS: Among 288 eligible interventions, variability in SBP was reduced after increased treatment with calcium channel blockers/diuretics versus both versus renin-angiotensin system inhibitors (-4.0 versus 6.9 versus 7.8%; P=0.015), primarily because of effects on maximum SBP (-4.6 versus -1.0 versus -1.0%; P=0.001), with no differences in effect on mean SBP. Class differences were greatest for early-morning SBP variability (3.6 versus 17.0 versus 38.3; P=0.002) and maximum (-4.8 versus -2.0 versus -0.7; P=0.001), with no effect on midmorning (P=0.29), evening (P=0.65), or diurnal variability (P=0.92). CONCLUSIONS: After transient ischemic attack or minor stroke, calcium channel blockers and diuretics reduced variability and maximum home SBP, primarily because of effects on morning readings. Home BP readings enable monitoring of response to SBP variability-directed treatment in patients with recent cerebrovascular events.

Validation of the Montreal cognitive assessment versus mini-mental state examination against hypertension and hypertensive arteriopathy after transient ischemic attack or minor stroke.

BACKGROUND AND PURPOSE: Lack of reduced cognitive impairment with blood pressure (BP) lowering in trials may reflect use of the Mini-Mental State Examination (MMSE), which is insensitive to mild cognitive impairment after cerebrovascular events compared with the Montreal Cognitive Assessment. We determined relationships between impairment on MMSE versus Montreal Cognitive Assessment (MoCA) with the major physiological determinant of vascular cognitive impairment: hypertension and hypertensive arteriopathy. METHODS: Cognitive impairment in consecutive patients 6 months after transient ischemic attack or minor stroke was defined as significant, mild, or none (MMSE<23, 23-26, ≥27; MoCA<20, 20-24, ≥25) and related to 20 premorbid systolic BP readings, home BP measurement (3 measurements, 3×daily for 1 month), and hypertensive arteriopathy (creatinine, stroke versus transient ischemic attack, leukoaraiosis) by ordinal regression. RESULTS: Of 463 patients, 45% versus 28% had at least mild cognitive impairment on the MoCA versus MMSE (P<0.001). Hypertensive arteriopathy was more strongly associated with cognitive impairment on the MoCA than MMSE (creatinine: odds ratio=3.99; 95% confidence interval, 2.06-7.73 versus 2.16, 1.08-4.33; event: 1.53, 1.06-2.19 versus 1.23, 0.81-1.85; leukoaraiosis: 2.09, 1.42-3.06 versus 1.34, 0.87-2.07). Premorbid and home BP measurement systolic BP were more strongly associated with impairment on vascular subdomains of the MoCA than MMSE (odds ratio/10 mm Hg: visuospatial 1.29 versus 1.05; attention 1.18 versus 1.07; language 1.22 versus 0.91; naming 1.07 versus 0.86). CONCLUSIONS: The stronger relationship between impairment on the MoCA with hypertensive arteriopathy, independent of age, indicates a greater sensitivity for vascular-origin cognitive impairment. Use of MoCA should improve sensitivity for cognitive impairment and treatment effects in future studies.