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

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

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

Targeted detection and repair of a spinal dural defect associated with successful biochemical resolution of subarachnoid bleeding in classical infratentorial superficial siderosis

BACKGROUND AND IMPORTANCE  : Classical infratentorial superficial siderosis (iSS) is characterised by repeated insidious bleeding into the subarachnoid space, leading to haemosiderin deposition within the subpial layers of the brainstem, cerebellum and spinal cord, sometimes with supratentorial involvement. Although nearly always associated with a dural defect (usually from previous trauma or neurosurgery) there is little evidence to support definitive investigation and management strategies. Here, we present a novel investigation strategy to identify a dural defect and subsequent successful surgical repair with biochemical resolution of subarachnoid bleeding. CLINICAL PRESENTATION: A 55-year-old gentleman presented with a 15-year progressive history of sensorineural deafness, followed by a slowly worsening gait ataxia. He had previously sustained cranio-spinal trauma. On examination there were features of myelopathy and ataxia. MRI demonstrated classical iSS, affecting cerebellum and cerebral cortices, with a cervicothoracic epidural CSF collection. Lumbar puncture (LP) revealed elevated ferritin 413 ng/mL and red cell count of 4160. Reverse CT myelography, a novel technique involving contrast injection into the collection, delineated a dural defect at the T9/T10 level that was not present on conventional myelography. Following surgical repair, repeat LP twelve months later demonstrated biochemical improvement (ferritin 18 ng/mL, red cells < 1). There was no further neurological deterioration in symptoms during eighteen months follow-up. CONCLUSION: We show the value of a rational targeted investigation pathway in identifying a surgically reparable dural defect underlying classical iSS. We also provide proof of concept that surgical repair can facilitate biochemical resolution of subarachnoid bleeding and might prevent progression of neurological disability

Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation : A European Stroke Organisation guideline

Patients with ischemic stroke or transient ischemic attack and non-valvular atrial fibrillation have a high risk of recurrent stroke and other vascular events. The aim of this guideline is to provide recommendations on antithrombotic medication for secondary prevention of stroke and other vascular outcomes in these patients. The working group identified questions and outcomes, graded evidence, and developed recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation approach and the European Stroke Organisation (ESO) standard operating procedure for guidelines. The guideline was reviewed and approved by the ESO guideline board and the ESO executive committee. In patients with atrial fibrillation and previous stroke or transient ischemic attack, oral anticoagulants reduce the risk of recurrence over antiplatelets or no antithrombotic treatment. Non-vitamin K antagonist oral anticoagulants are preferred over vitamin K antagonists because they have a lower risk of major bleeding and death. Recommendations are weak regarding timing of treatment, (re-)starting oral anticoagulants in patients with previous intracerebral haemorrhage, and treatment in specific patient subgroups of those of older age, with cognitive impairment, renal failure or small vessel disease, because of a lack of strong evidence. In conclusion, for patients with atrial fibrillation and ischemic stroke or transient ischemic attack, non-vitamin K antagonist oral anticoagulants are the preferred treatment for secondary prevention of recurrent stroke or thromboembolism. Further research is required to determine the best timing for initiating oral anticoagulants after an acute ischemic stroke, whether or not oral anticoagulants should be (re)started in patients with a history of intracerebral haemorrhage, and the best secondary preventive treatment in specific subgroups.Peer reviewe

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH)

PURPOSE: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100 mg subcutaneous anakinra within 8 h of onset, followed by five, 12-hourly, 100 mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72 h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6). FINDINGS: 25 patients (target = 80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6 ml, interquartile range[IQR]:4.8-17.9) versus placebo (5.5 ml, IQR:2.1-10.9). Adjusting for baseline, 72 h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: -0.17-0.06, p = 0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%-80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra. CONCLUSION: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required

Classical infratentorial superficial siderosis of the central nervous system: pathophysiology, clinical features and management

The term superficial siderosis (SS) is derived from the Greek word 'sideros', meaning iron. It includes two subtypes, distinguished by their anatomical distribution, causes and clinical features: 'classical' infratentorial SS (iSS, which sometimes also affects supratentorial regions) and cortical SS (cSS, which affects only supratentorial regions). This paper considers iSS, a potentially disabling disorder usually associated with very slow persistent or intermittent subarachnoid bleeding from a dural defect, and characterised by progressive hearing and vestibular impairment, ataxia, myelopathy and cognitive dysfunction. The causal dural defect-most often spinal but sometimes in the posterior fossa-typically follows trauma or neurosurgery occurring decades before diagnosis. Increasing recognition of iSS with paramagnetic-sensitive MRI is leading to an unmet clinical need. Given the diagnostic challenges and complex neurological impairments in iSS, we have developed a multidisciplinary approach involving key teams. We discuss pathophysiology, diagnosis and management of iSS, including a proposed clinical care pathway

Clinical considerations in early-onset cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is an important cerebral small vessel disease associated with brain haemorrhage and cognitive change. The commonest form, sporadic amyloid-beta CAA, usually affects people in mid- to later life. However, early-onset forms, though uncommon, are increasingly recognised and may result from genetic or iatrogenic causes that warrant specific and focussed investigation and management. In this review, we firstly describe the causes of early-onset CAA, including monogenic causes of amyloid-beta CAA (APP missense mutations and copy number variants; mutations of PSEN1 and PSEN2) and non-amyloid-beta CAA (associated with ITM2B, CST3, GSN, PRNP and TTR mutations), and other unusual sporadic and acquired causes including the newly-recognised iatrogenic subtype. We then provide a structured approach for investigating early-onset CAA, and highlight important management considerations. Improving awareness of these unusual forms of CAA amongst healthcare professionals is essential for facilitating their prompt diagnosis, and an understanding of their underlying pathophysiology may have implications for more common, late-onset, forms of the disease