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

Cerebral small vessel disease and intracranial bleeding risk: prognostic and practical significance

Balancing the risks of recurrent ischaemia and antithrombotic-associated bleeding, particularly intracranial haemorrhage (ICH), is a key challenge in the secondary prevention of ischaemic stroke and transient ischaemic attack. In hyperacute ischaemic stroke, the use of acute reperfusion therapies is determined by the balance of anticipated benefit and the risk of ICH. Cerebral small vessel disease (CSVD) causes most spontaneous ICH. Here, we review the evidence linking neuroimaging markers of CSVD to antithrombotic and thrombolytic-associated ICH, with emphasis on cerebral microbleeds (CMB). We discuss their role in the prediction of ICH, and practical implications for clinical decision making. Although current observational data suggests CMB presence should not preclude antithrombotic therapy in patients with ischaemic stroke or TIA, they are useful for improving ICH risk prediction with potential relevance for determining the optimal secondary prevention strategy, including the use of left atrial appendage occlusion. Following ICH, recommencing antiplatelets is probably safe in most patients, while the inconclusive results of recent randomised controlled trials of anticoagulant use makes recruitment to ongoing trials (including those testing left atrial appendage occlusion) in this area a high priority. Concern regarding CSVD and ICH risk after hyperacute stroke treatment appears to be unjustified most patients, though some uncertainty remains regarding patients with very high CMB burden and other risk factors for ICH. We encourage careful phenotyping for underlying CSVD in future trials, with potential to enhance precision medicine in stroke

Relationships between intracranial arterial dolichoectasia and small vessel disease in patients with ischaemic stroke: a systematic review and meta-analysis

BACKGROUND: Intracranial arterial dolichoectasia (IADE) is a common arterial finding of dilation, elongation, or both, affecting large intracranial vessels, and associated with vascular risk factors, including hypertension. Associations of IADE with neuroimaging cerebral small vessel disease (CSVD) may be relevant for diagnosis and prognosis in patients with stroke. The study aimed to conduct an updated systematic review and meta-analysis of observational studies to investigate the relationships of IADE with well-defined CSVD markers in patients with ischaemic stroke. METHODS: We systematically searched PubMed, Embase, and Scopus for studies on IADE in ischaemic stroke patients with fulfilling predefined inclusion criteria. We pooled data to conduct a meta-analysis to compare the prevalence of SVD markers between patients with and without IADE groups using risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: From 157 retrieved abstracts, we included six studies from seven publications comprising 6102 patients with ischaemic stroke. The mean age of patients was 52.8 years, and 3691 (60.5%) were male. IADE was diagnosed in 11.4% (95% CI 8.9-13.9) (761) of included patients; 51.8% (3160) had hypertension. Compared to patients without IADE, individuals diagnosed with IADE had a significantly increased prevalence of lacune (RR 1.67, 95% CI 1.36-2.06, P < 0.01, I2 = 0.00%), cerebral microbleeds (CMBs) (RR 2.56, 95% CI 1.53-4.28, P < 0.01, I2 = 84.95%) and white matter hyperintensities (WMHs) (RR 2.17, 95% CI 1.84-2.56, P < 0.01, I2 = 0.00%). CONCLUSIONS: In patients with ischaemic stroke, IADE is associated with a higher prevalence of CSVD markers, including lacunes, CMBs, and WMHs. Further studies are needed to clarify the mechanisms underlying these associations and their potential relevance for the understanding, diagnosis, and treatment of CSVD

Cognitive dysfunction in patients with cerebral microbleeds on T2*-weighted gradient-echo MRI.

Gradient echo T2*-weighted MRI has high sensitivity in detecting cerebral microbleeds, which appear as small dot-like hypointense lesions. Microbleeds are strongly associated with intracerebral haemorrhage, hypertension, lacunar stroke and ischaemic small vessel disease, and have generated interest as a marker of bleeding-prone microangiopathy. Microbleeds have generally been considered to be clinically silent; however, since they are located in widespread cortical and basal ganglia regions and are histologically characterized by tissue damage, we hypothesized that they would cause cognitive dysfunction. We therefore studied patients with microbleeds (n = 25) and a non-microbleed control group (n = 30) matched for age, gender and intelligence quotient. To avoid the confounding effects of coexisting cerebrovascular disease, the groups were also matched for the extent of MRI-visible white matter changes of presumed ischaemic origin, location of cortical strokes, and for the proportion of patients with different stroke subtypes (including lacunar stroke). A battery of neuropsychological tests was used to assess current intellectual function, verbal and visual memory, naming and perceptual skills, speed and attention and executive function. Microbleeds were most common in the basal ganglia but were also found in frontal, parieto-occipital, temporal and infratentorial regions. There was a striking difference between the groups in the prevalence of executive dysfunction, which was present in 60% of microbleed patients compared with 30% of non-microbleed patients (P = 0.03). Logistic regression confirmed that microbleeds (but not white matter changes) were an independent predictor of executive impairment (adjusted odds ratio = 1.32, 95% confidence interval 1.01-1.70, P = 0.04). Patients with executive dysfunction had more microbleeds in the frontal region (mean count 1.54 versus 0.03; P = 0.002) and in the basal ganglia (mean 1.17 versus 0.32; P = 0.048). There was a modest correlation between the number of microbleeds and the number of cognitive domains impaired (r = 0.44, P = 0.03). This study provides novel evidence that microbleeds are associated with cognitive dysfunction, independent of the extent of white matter changes of presumed ischaemic origin, or the presence of ischaemic stroke. The striking effect of microbleeds on executive dysfunction is likely to result from associated tissue damage in the frontal lobes and basal ganglia. These findings have implications for the diagnosis of stroke patients with cognitive impairment, and for the appropriate use of antihypertensive and antiplatelet treatments in these patients

Long-term use benefits of personal frequency-modulated systems for speech in noise perception in patients with stroke with auditory processing deficits: a non-randomised controlled trial study.

OBJECTIVES: Approximately one in five stroke survivors suffer from difficulties with speech reception in noise, despite normal audiometry. These deficits are treatable with personal frequency-modulated systems (FMs). This study aimed to evaluate long-term benefits in speech reception in noise, after daily 10-week use of personal FMs, in non-aphasic patients with stroke with auditory processing deficits. DESIGN: This was a prospective non-randomised controlled trial study. Patients were allocated to an intervention care group or standard care subjects group according to their willingness to use the intervention or not. SETTING: Tertiary care setting. PARTICIPANTS: Nine non-aphasic subjects with ischaemic stroke, normal/near-normal audiometry and auditory processing deficits and with reported difficulties understanding speech in background noise were recruited in the subacute stroke stage (3-12 months after stroke). INTERVENTIONS: Four patients (intervention care subjects) used the FMs in their daily life over 10 weeks. Five patients (standard care subjects) received standard care. PRIMARY OUTCOME MEASURES: All subjects were tested at baseline (visit 1) and 10 weeks later (visit 2) on a sentences in noise test with the FMs (aided) and without the FMs (unaided). RESULTS: Speech reception thresholds showed clinically and statistically significant improvements in intervention but not in standard care subjects at 10 weeks in aided and unaided conditions. CONCLUSIONS: 10-week use of FMs by adult patients with stroke may lead to benefits in unaided speech in noise perception. Our findings may indicate auditory plasticity type changes and require further investigation. TRIAL REGISTRATION NUMBER: Pre-results; NCT02889107

Long-term use benefits of personal frequency-modulated systems for speech in noise perception in patients with stroke with auditory processing deficits: a non-randomised controlled trial study.

OBJECTIVES: Approximately one in five stroke survivors suffer from difficulties with speech reception in noise, despite normal audiometry. These deficits are treatable with personal frequency-modulated systems (FMs). This study aimed to evaluate long-term benefits in speech reception in noise, after daily 10-week use of personal FMs, in non-aphasic patients with stroke with auditory processing deficits. DESIGN: This was a prospective non-randomised controlled trial study. Patients were allocated to an intervention care group or standard care subjects group according to their willingness to use the intervention or not. SETTING: Tertiary care setting. PARTICIPANTS: Nine non-aphasic subjects with ischaemic stroke, normal/near-normal audiometry and auditory processing deficits and with reported difficulties understanding speech in background noise were recruited in the subacute stroke stage (3-12 months after stroke). INTERVENTIONS: Four patients (intervention care subjects) used the FMs in their daily life over 10 weeks. Five patients (standard care subjects) received standard care. PRIMARY OUTCOME MEASURES: All subjects were tested at baseline (visit 1) and 10 weeks later (visit 2) on a sentences in noise test with the FMs (aided) and without the FMs (unaided). RESULTS: Speech reception thresholds showed clinically and statistically significant improvements in intervention but not in standard care subjects at 10 weeks in aided and unaided conditions. CONCLUSIONS: 10-week use of FMs by adult patients with stroke may lead to benefits in unaided speech in noise perception. Our findings may indicate auditory plasticity type changes and require further investigation. TRIAL REGISTRATION NUMBER: Pre-results; NCT02889107

Health-Related Quality of Life in Adults With Classical Infratentorial Superficial Siderosis: A Cross-sectional Study

BACKGROUND AND OBJECTIVES: Infratentorial superficial siderosis (iSS) is a rare but disabling neurological condition characterised by progressive hearing loss, balance and mobility problems. The functional decline in these neurological domains with iSS progression is likely to adversely impact health-related quality of life (HRQoL). We studied HRQoL of adults with iSS using two common generic HRQoL measures (Health Utilities Index Mark III (HUI3) and EuroQoL EQ5D (5 Level) to determine the most impacted domains and evaluate the association between HRQoL scores and disease duration. METHODS: This observational study was an anonymous online survey. Following institutional Research Ethics Committee approval, we contacted dedicated international organisations, charities and patient-groups identified through online searches, social media and collaborative networks, to distribute the study information and study link, inviting their members diagnosed with iSS to participate. Participation required access to a digital device connected to the internet, confirmation of eligibility (aged ≥18 years and previously diagnosed with iSS) and informed consent to participate in the survey, which included study-specific questions (demographics, iSS, hearing) and HRQoL questionnaires. Survey responses were captured by the Research Electronic Data Capture (REDCap) survey software and analysed using the SPSS statistical package. Linear regression analysis was performed to investigate the association between HRQoL scores and disease duration. RESULTS: Of fifty participants,60% were male; the median (interquartile range, IQR) age was 60 (15) years. The median (IQR) multi-attribute scores for HUI3 and EQ5D were 0.36 (0.53) and 0.64 (0.33), respectively. The most frequently affected domains (moderate or worse category) were hearing (64%), and pain (48%) for HUI3, and mobility (54%) and pain (50%) for EQ5D. There was a weak association between disease duration and multi-attribute scores for HUI3 (R=0.353; adjusted R2=0.096; b=-0.008; p=0.047) but not EQ5D. DISCUSSION: Our findings demonstrate low HRQoL scores which capture low functional status in several domains typically affected in iSS, suggesting that iSS has a major adverse impact on quality of life in multiple functional domains. Measures of HRQoL in iSS should be included in clinical and research settings, including treatment trials

A survey of opinion: When to start oral anticoagulants in patients with acute ischaemic stroke and atrial fibrillation?

Background: There is uncertainty regarding the optimal timing for initiation of oral anticoagulant treatment (OAC) in patients with recent ischaemic stroke and atrial fibrillation (AF). We surveyed the current UK practice and assessed clinician’s opinions of when to use OAC in recent stroke patients with AF. Methods: An online survey was sent to stroke physicians within the United Kingdom via their national societies. Results: One hundred and twenty-one clinicians responded to the survey. Ninety-five percent of responders agreed there was uncertainty regarding timing of OAC initiation after AF-related ischaemic stroke. Thirty-six percent of responders followed the ‘1-3-6-12’ European Society of Cardiology (ESC) guidelines recommendation. Uncertainty was greater in cases of moderate stroke than in cases of TIA, mild or severe stroke. Eighty-eight percent of responders would be willing to participate in a clinical trial of early vs. later initiation of OAC after stroke. Direct-acting oral anticoagulant (DOAC) were the preferred OAC of choice. Conclusion: There is a lack of consensus amongst stroke physicians for when to initiate OAC to prevent recurrence in stroke patients with AF. There is little uncertainty regarding TIA. A clinical trial assessing use of early vs. later initiation of DOAC in patients with recent ischaemic stroke and AF would be beneficial

A Hearing Screening Protocol for Stroke Patients: An Exploratory Study.

Background: Auditory impairment post stroke is common and may be due to both peripheral hearing loss and or central auditory processing disorder (CAPD). When auditory impairment remains untreated, it may impact on patient communication and rehabilitation after stroke. Offering a comprehensive audiological assessment to all stroke patients would be both costly and time-consuming. A brief hearing screening is thus required. Objective: The aim of this study was to determine whether a two-tiered hearing screening approach, with use of a handheld hearing screener and two validated hearing questionnaires could be used as a hearing screening for peripheral hearing loss and CAPD in stroke survivors. The sensitivity and specificity of the screening method was analyzed. Methods: This was a prospective study conducted in a tertiary neurology hospital. Forty-two consecutive stroke patients were recruited and tested within 3-12 months post-onset of their stroke. Three screening tools for the identification of hearing impairment were evaluated in this study: A handheld hearing screener for determination of peripheral audiometric hearing loss and two validated questionnaires (The Amsterdam Inventory Auditory for Disability (AIAD) and the Hearing Handicap Inventory for Elderly (HHIE) questionnaires) for determination of peripheral hearing loss and/or CAPD. Results: The hearing screener had a sensitivity of 92. 59% detecting a hearing loss and specificity of 100%. The greatest test accuracy in identifying a central auditory processing type hearing impairment in stroke patients was found when the handheld hearing screener and the AIAD questionnaire were combined. Conclusion: This study is a first step toward addressing the complex auditory needs of stroke survivors in a systematic manner, with the ultimate aim to support their communication needs and long-term recovery and wellbeing. Registration: Project Identification number 11/0469 and REC ref 11/LO/1675