But they tend to worsen and become irreversible during the normal course of the disease. Sachdev P, Kalaria R, OBrien J, Skoog I, Alladi S, Black SE, et al. 57. 10. Further work is needed to understand the pathophysiology of SVD, using advanced preclinical, neuroimaging, and pathological research methods. Genetic and lifestyle, 77. They also get small amounts of EPA and DHA. Oudeman EA, Greving JP, Van den Berg-Vos RM, Biessels GJ, Bron EE, van Oostenbrugge R, et al. Keyword Highlighting Clarkson BD, Griffiths D, Resnick NM. A subgroup analysis from the randomized, controlled RESTART trial reported that individuals with a history of ICH taking antiplatelets in the presence of CMB did not experience increased hazard (hazard ratio [HR] 0.30, 95% CI 0.081.13 vs. 0.7, 95% CI 0.134.61). Engage in different types of exercise that improve your balance, strength and heart health. 4Stroke, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, UK. Han SW, Song TJ, Bushnell CD, Lee SS, Kim SH, Lee JH, et al. [120] Despite, ISMN being commonly used in the management of ischemic heart disease, data regarding its use in SVD and stroke are scanty. CNS small vessel disease: A clinical review. [35] There is increasing recognition that its multidomain involvement extends beyond stroke and dementia [Figure 1] to include gait and balance dysfunction, behavioral and neuropsychiatric symptoms, and subtle, non-focal neurological features [Figure 2],[68] resulting in presentations to diverse general and specialist services [Table 1]. Biffi A, Greenberg SM. We support close liaison with patients, family members and general practitioners to monitor for clinical deterioration. A comparison of location of acute symptomatic versus 'silent small vessel lesions. doi: 10.1097/CM9.0000000000001177, This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. [49] Neuroimaging is particularly important for distinguishing SVD-related VCI, where stepwise cognitive decline is often absent, instead characterized by insidious, fluctuating cognitive decline, punctuated by neurological deficits [Figure 3]. they have multiple causes). In the atherosclerosis risk in communities (ARIC) study, high triglycerides increased the risk of incident lacunes (OR 1.24, 95% CI 1.041.47), while elevated high-density lipoproteins (HDL) reduced the risk (OR 0.77, 95% CI 0.590.99). Neuropsychiatric symptoms are common post-stroke and in individuals with vascular dementia, but whether there is a shared neuroanatomical substrate remain unclear and longitudinal studies are sparse. Here we present an evidence-based overview of the literature on clinical aspects of SVD, discussed in the context of our clinical and research experience of caring for these patients. Effect of a 24-month physical activity program on brain changes in older adults at risk of Alzheimer's disease: the AIBL active trial. Age-related changes of peak width skeletonized mean diffusivity (PSMD) across the adult lifespan: a multi-cohort study. The Fazekas scale is commonly used to evaluate WMH on MRI and can be used on CT.[78] Similarly, while less sensitive than MRI-based scores, equivalent CT-based scores for total SVD and brain frailty[29] predict poor functional outcome and cognitive impairment after stroke. Rajani RM, Quick S, Ruigrok SR, Graham D, Harris SE, Verhaaren BFJ, et al. Talk to your doctor about your concerns. Brain ischemia can be categorized into a few different types. 19. Know your cholesterol levels and blood pressure. WebCOL4A1 -related brain small-vessel disease is part of a group of conditions called the COL4A1 -related disorders. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598791/). Key ingredients: RAW resveratrol blend, RAW organic antioxidant blend and RAW probiotic and enzyme blend. 31. 92. Staals J, Makin SDJ, Doubal F, Dennis M, Wardlaw JM. Appleton JP, Woodhouse LJ, Adami A, Becker JL, Berge E, Cala LA, et al. Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, Antikainen R, et al. 118. Vascular subcortical dementias: clinical aspects. [100] Similarly, a meta-analysis of trials including 1,369 patients with prior stroke found less WMH progression (standardized mean difference 0.19; 95% CI 0.32 to 0.06; I2 = 20%) with intensive BP lowering as compared with usual care. Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral. Instead, it seems to be important to have an adequate vitamin D intake (from the sun, diet and dietary [1,2] The core clinical manifestations include lacunar ischemic stroke, intracerebral hemorrhage and cognitive decline, including vascular cognitive impairment and amplification of pathological and cognitive Alzheimer's disease manifestations. We searched Ovid MEDLINE using the terms Cerebral Small Vessel Diseases/ or White matter hyperintens and Clinical from inception to April 3, 2020. Kuchel GA, Moscufo N, Guttmann CR, Zeevi N, Wakefield D, Schmidt J, et al. [84] A trial of 80 patients with ischemic stroke (1/2 lacunar etiology) demonstrated reduced BP, augmentation index and carotid intima-media thickness progression following one year of receiving allopurinol. Cilostazol for secondary prevention of, 108. Cavalieri M, Schmidt R, Chen C, Mok V, de Freitas GR, Song S, et al. 35. Cerebral small vessel disease is a very common condition among the elderly that affects the small modify the keyword list to augment your search. B-vitamins have anti-inflammatory properties and act in protective roles against neurodegenerative mechanisms, for example, through modulation of the Read Reviews (80) Treatment name Should computed tomography appearance of lacunar, 26. The work cannot be changed in any way or used commercially without permission from the journal. Once the brain cells have been lost, they do not come back. 73. It requires more clinical trials in order to improve pharmacological interventions, lifestyle and dietary modifications. Supportive findings on neuroimaging raise diagnostic certainty from possible to probable when there is no clear temporal relationship to stroke events,[44] although the extent of radiological SVD considered sufficient to contribute to a VCI diagnosis is debated. Whether unusual sleep patterns increase the risk of SVD lesions is unclear although disordered night-time sleep is associated with brain atrophy and increased daytime sleep is associated with increased PVS on MRI. This work is supported by the UK Dementia Research Institute (JMW, CA) which receives its funding from DRI Ltd, funded by the UK MRC, Alzheimer's Society and Alzheimer's Research UK; the Fondation Leducq Network for the Study of Perivascular Spaces in Small Vessel Disease (JMW; 16 CVD 05); The European Union Horizon 2020, [emailprotected] (JMW, FD, PHC-03-15, project No 666881); The Row Fogo Charitable Trust Centre for Research into Aging and the Brain (JMW); The British Heart Foundation (LACI-2 and Centre for Research Excellence; CS/15/5/31475, RE/18/5/34216); The Chief Scientist Office of Scotland (CZB/4/281, ETM/326, and Clinical Academic Fellowship UC; CAF/18/08); Chest Heart Stroke Scotland (Res14/A157); NHS Research Scotland (FND); Stroke Association (Garfield Weston Foundation Senior Clinical Lectureship FND, TSALECT 2015/04; Small Vessel Disease-Spotlight on Symptoms, FD, JMW, UC, SVD-SOS; SAPG 19\100068; R4VaD, JMW, FD, PMB, 16 VAD 07; Princess Margaret Research Development Fellowship, UC, 2018; and Stroke Association Professor of Stroke Medicine PMB); PMB is a NIHR Senior Investigator. Statins for asymptomatic middle cerebral artery stenosis: the regression of cerebral artery stenosis study. Low levels of B12 have been associated with more severe WMH. Bleeding in your brains small blood vessels (cerebral microbleeds). Staekenborg SS, van der Flier WM, van Straaten EC, Lane R, Barkhof F, Scheltens P. Neurological signs in relation to type of cerebrovascular disease in vascular. Diffusion-weighted MRI in vascular. [108] The ongoing LACI-2 trial is also assessing ISMN and its effects on safety and efficacy in clinical and radiological outcomes. B vitamins and. Hence, we report several outcomes depending on available data. We need more trials of medications and simple lifestyle modifications, or combinations thereof. National Institutes of Health; National Heart, Lung and Blood Institute. Incidence of brain infarcts, cognitive change, and risk of, 47. While some lesions are truly clinically silent, for instance if small or located in less eloquent regions,[13] careful questioning about historical stroke or transient ischemic attack (TIA) symptoms is recommended, as a positive history may render such individuals eligible for secondary stroke prevention. A new study has found numerous changes in gene activity in affected small blood vessels in the brain, that may provide targets for drug therapy to improve recovery from stroke. 113. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. 11. Karama S, Ducharme S, Corley J, Chouinard-Decorte F, Starr J, Wardlaw JM, et al. WebTreatment name CITICOLINE. In advancing disease, onwards referral to relevant services should be considered to maximize independence including cognitive clinics, physiotherapists, occupational therapists, and social care. Patients have typically presented to different clinical services or been recruited into research focused on one clinical manifestation, perhaps explaining a lack of awareness, until recently, of the full range and complexity of SVD. This approach should integrate clinical expertise in stroke neurology, cognitive, and physical dysfunctions. Resistance training and white matter lesion progression in older women: exploratory analysis of a 12-month randomized controlled trial. 105.ten Dam VH, van den Heuvel DM, van Buchem MA, Westendorp RG, Bollen EL, Ford I, et al. De Guio F, Duering M, Fazekas F, De Leeuw FE, Greenberg SM, Pantoni L, et al. WebB-vitamin supplementation with folate and vitamins B12 and B6 reduces homocysteine concentrations. Effectiveness? Adopting healthy habits, such as exercising and eating more nutrients. The chances of having the condition increase with age. A cup of wild blueberries is not only a tasty, low-calorie snack, but it also lowers blood pressure, improves blood vessel function and provides a small brain boost, Bos D, Wolters FJ, Darweesh SKL, Vernooij MW, de Wolf F, Ikram MA, et al. There is inadequate evidence to determine whether other symptoms including delusions or emotional lability are associated with SVD due to insufficient data and mixed approaches to symptom assessments. Wardlaw JM, Chappell FM, Valdes Hernandez MDC, Makin SDJ, Staals J, Shuler K, et al. Lower urinary tract. [42,43] These findings need to be reproduced in large prospective blinded studies, adjusting for mobility, frailty and co-morbidities. [118] A meta-analysis including 10,449 patients with prior ischemic stroke, predominantly from the South Asian-Pacific region, found that cilostazol reduced recurrent ischemic stroke (OR 0.68, 95% CI 0.57 to 0.81), intracerebral hemorrhage (OR 0.43, 95% CI 0.29 to 0.64), and death (OR 0.64, 95% CI 0.49 to 0.83) as compared with either placebo, aspirin or clopidogrel. Brain activity during bladder filling is related to white matter structural changes in older women with urinary incontinence. It can be useful to work with a physical therapist or fitness trainer. Cerebral. Mok VC, Lam WW, Fan YH, Wong A, Ng PW, Tsoi TH, et al. Hasel P, Dando O, Jiwaji Z, Baxter P, Todd AC, Heron S, et al. Risk factors for progression in SVD include traditional vascular risk factors such as age and hypertension, and MRI biomarkers, which not only represent the cornerstone for SVD diagnosis but also identify risk of progression, provide a feasible strategy for monitoring patients, and a therapeutic target. Talk to your healthcare provider about developing a personalized plan for you. 80. An essential prerequisite to accelerating clinical trials is to improve the consistency, and standardization of clinical, cognitive and neuroimaging endpoints. 24. WebB-vitamin supplementation with folate and vitamins B12 and B6 reduces homocysteine concentrations. [6971] Alcohol intake is associated with worse WMH in patients with minor stroke. Highlight selected keywords in the article text. Lacunar stroke clinical syndrome (LACS) is a key SVD manifestation. We should devise electronic record-based alerts based on notification of relevant healthcare referrals [Table 1], combined with existing imaging data. These medications can We should devise composite prediction scores of SVD progression for use as screening tools in everyday clinical settings, incorporating available symptom, risk factor, cognitive, demographic, and imaging reports, similar to those used for estimating cardiovascular or fracture risks. Efficacy of nitric oxide, with or without continuing antihypertensive, 111. Croall ID, Tozer DJ, Moynihan B, Khan U, Obrien JT, Morris RG, et al. Cerebral small vessel disease (CSVD) is common among older adults, but its causes and connections to other brain diseases like Alzheimers arent well understood. PMB has received honoraria as Chief Investigator or Steering Committee Chair of trials (DiaMedica, Phagenesis) and attending Advisory Boards (Moleac, Nestle, Sanofi). Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism. Ahmad H, Cerchiai N, Mancuso M, Casani AP, Bronstein AM. https://betterhealthwhileaging.net/cerebral-small-vessel-disease Clinical management of cerebral small vessel disease: a call for a holistic approach. Age-related decline in oligodendrogenesis retards white matter repair in mice. 17. inability to independently manage one's finances. Gait and balance dysfunction, shortened stride length (n = 431),[6] unexplained dizziness (n = 122),[31] falls (n = 187),[32] and features of vascular parkinsonism such as bradykinesia, rigidity, and gait disturbances (n = 503 community-dwelling)[33] are all associated with SVD. Further discrimination between mild cognitive impairment and dementia is based on whether cognition is sufficiently impaired to result in loss of functional independence. This includes rigorous management of modifiable risk factors including smoking cessation, dietary improvements, and appropriate evidence-based medications while balancing risks of side effects. Marie P. Des foyers lacunaires de dsintgration et de diffrents autres tats cavitaires du cerveau. Makin SD, Doubal FN, Shuler K, Chappell FM, Staals J, Dennis MS, et al. Type 2 diabetes, change in depressive, 65. Unlike large vessels, it is a challenge to visualize small vessels in vivo, hence the difficulty to directly monitor the natural Experts arent exactly sure what causes microvascular ischemic disease. Contact Us, By continuing to browse this site, you agree to our, help their parents with cognitive decline, Changes in white matter as determinant of global functional decline in older independent outpatients, associated with a higher risk of depression, How to Address Cardiovascular Risk Factors for Better Brain Health: 12 Risks to Know & 5 Things to Do, 6 Steps to Better High Blood Pressure Treatment for Older Adults, The relation between antihypertensive treatment and progression of cerebral small vessel disease, careful evaluation for cognitive impairment, CNS small vessel disease: A clinical review, Mechanisms underlying sporadic cerebral small vessel disease: insights from neuroimaging, Causes and consequences of cerebral small vessel disease. Gyanwali B, Shaik MA, Tan BY, Venketasubramanian N, Chen C, Hilal S. 56. Heye AK, Thrippleton MJ, Chappell FM, Valdes Hernandez MC, Armitage PA, Makin SD, et al. Rensma SP, van Sloten TT, Ding J, Sigurdsson S, Stehouwer CD, Gudnason V, et al. These may include support groups and one-on-one counseling. So, its important to go to the emergency room immediately if youre experiencing sudden: Microvascular ischemic disease can range from mild to severe. Banerjee G, Carare R, Cordonnier C, Greenberg SM, Schneider JA, Smith EE, et al. 8.van Rooij FG, Vermeer SE, Goraj BM, Koudstaal PJ, Richard E, de Leeuw FE, et al. Wehrberger C, Jungwirth S, Fischer P, Tragl KH, Krampla W, Marlies W, et al. [121] A substudy from the VITATOPS trial suggested that patients with severe WMH who received B vitamins for 2 years had slower WMH progression.[112]. These include: 2. [17,50,5456], The most important modifiable vascular risk factor for SVD is arterial hypertension (defined as blood pressure greater than 140/90 mmHg). 14. Sudden urge to urinate (urinary urgency). [57] Ambulatory blood pressure (BP) provides more accurate data on BP status than office-based BP measurements and may help BP control in patients with extensive SVD. Sweeney MD, Montagne A, Sagare AP, Nation DA, Schneider LS, Chui HC, et al. Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment. Localization of brain white matter hyperintensities and urinary incontinence in community-dwelling older adults. [7,15] How patients report, and clinicians interpret, these symptoms is poorly understood and inter-individual factors influencing accurate reporting are complex. Vitamin K2 as MK-7 is the only compound to date shown to impact arterial calcification through its activation of MGP, which is why it is garnering attention from the medical community as a potential therapy, says Christopher Speed, Senior Vice President of Global Sales and Marketing with NattoPharma, the world leaders in vitamin K2 research 36. Microvascular ischemic disease affects about 5% of people who are 50 years old. 66. 48. Abrupt cognitive impairment due to single strategic small subcortical infarcts has been described rarely,[47] is understudied, and requires further characterization. 119. [50] SVD is associated with longer hospital lengths of stay in cognitively impaired,[51] and earlier institutionalization in stroke patients.[52]. 122. A trial of two repurposed licenced drugs to prevent progression of cerebral, 110. Aspirin. Aspirin can limit inflammation and prevent blood clots. Metformin. This drug is typically prescribed to lower blood sugar in people with diabetes, but it can improve blood vessel health even in those who don't have diabetes. If you're diagnosed with small vessel disease, you'll need regular checkups with your health care provider. Understanding the role of the perivascular space in cerebral. Blair GW, Appleton JP, Flaherty K, Doubal F, Sprigg N, Dooley R, et al. Hilal S, Mok V, Youn YC, Wong A, Ikram MK, Chen CL. Urinary complaints in nondisabled elderly people with age-related white matter changes: the Leukoaraiosis And DISability (LADIS) Study. 2 Turmeric Westend61 / Getty Images Reviews. Itoh Y, Yamada S, Konoeda F, Koizumi K, Nagata H, Oya M, et al. Further, detailed, observational research on modifiable and non-modifiable factors is required, integrating these into clinical trial design, determining whether using different treatment strategies for individuals with non-modifiable risk factors produces any additional benefit. Brain hemorrhage. Ling Y, Chabriat H. Incident cerebral lacunes: a review. Ogama N, Yoshida M, Nakai T, Niida S, Toba K, Sakurai T. Frontal white matter hyperintensity predicts lower urinary tract dysfunction in older adults with amnestic. The previously mentioned LACI-1 trial randomized patients to ISMN, in addition to Cilostazol, in a factorial design. 38. Cerebrovascular Diseases and Critical Care Overview Print People who have strokesand other brain and blood vessel conditions (cerebrovascular diseases) benefit from being evaluated and treated by the doctors of the specialty group for cerebrovascular diseases and critical care. [4,18,19] Other neurological symptoms associated with SVD include dysphagia,[20] dysarthria,[21] pyramidal tract signs, and pseudobulbar palsy.[22]. Sleep and brain morphological changes in the eighth decade of life. Wolters Kluwer Health Aribisala BS, Riha RL, Valdes Hernandez M, Munoz Maniega S, Cox S, Radakovic R, et al. Prof. Wardlaw emphasizes, "Encouragingly, exercise and a healthy Mediterranean diet with folic acid and vitamin B12, combined with guideline-based Venkatraman VK, Sanderson A, Cox KL, Ellis KA, Steward C, Phal PM, et al. [106], Cilostazol, a phosphodiesterase 3 inhibitor, is commonly used for stroke prevention in the Asia-Pacific region. Conflicts of interest: The authors declare academic grants for research as listed above; JMW chairs the ESOC 2021 Planning Group, and participates in two ESO Guidelines; CA, JPA and UC have no conflicts to disclose. Despite being almost ubiquitous in brain imaging, the clinicoradiologic association of small vessel disease is weak, and the underlying pathogenesis is poorly understood. Severity of white matter hyperintensities and length of hospital stay in patients with cognitive impairment: a CREDOS (Clinical Research Center for, 52. But it affects almost 100% of people older than 90. The results of the MRI are needed to decide on how to treat the person. Regular exercise, healthy diet (Mediterranean diet, folic acid and vitamin B12),[68] and avoiding adverse lifestyle factors such as smoking, excess alcohol or high dietary sodium, are all associated with having fewer SVD features in observational studies. Regenhardt RW, Das AS, Lo EH, Caplan LR. Although SVD lesions were previously considered to be focal and permanent, it is now clear that they represent more dynamic global disease. We do not endorse non-Cleveland Clinic products or services. Plasma vitamin B12 status and cerebral white-matter lesions. Prevention of, 15. Primary treatment options for small vessel disease involve medications that relieve pain, treat risk factors, and manage associated symptoms. Since it is currently difficult to identify individuals whose small vessels may be particularly sensitive to even minor BP elevations, it remains uncertain how intensively blood pressure should be lowered. 121.de Lau LM, Smith AD, Refsum H, Johnston C, Breteler MM. Fandler S, Gattringer T, Eppinger S, Doppelhofer K, Pinter D, Niederkorn K, et al. This is easy to do since people may attribute symptoms to normal signs of aging. non-specific reports of not managing at home or deficits in instrumental activities of daily living, e.g. Debette S, Schilling S, Duperron MG, Larsson SC, Markus HS. Bath PM, Scutt P, Anderson CS, Ankolekar S, Appleton JP, Berge E, et al. 71. 90. We note wide variability in choice and definitions of end-points used in trials in SVD that would benefit from some standardization. Read Reviews (200) For instance, a threshold effect of sufficient SVD burden might accumulate before triggering symptoms[16] and this might vary between individuals and at different ages [Figure 4]. Methods: In fact, a research review published in 2017, suggests sage contains compounds that may be beneficial for cognitive and neurological function. Other studies have also found that eating blueberries or blueberry compounds known as anthocyanins improves vascular function. In 2 clinical trials, one with 79 and the other with 86 subjects with high blood pressure, the [83] Since WMH may have some clinically meaningful reversible components,[81,82] the concept that prevention of worsening WMH-related brain damage may translate into long-term benefits for brain health is important. Fanning JP, Wong AA, Fraser JF. Saini M, Ikram K, Hilal S, Qiu A, Venketasubramanian N, Chen C. Silent. 106. Clinical management of cerebral small vessel disease: a call for a holistic approach. Effects of statins on the progression of cerebral white matter lesion: Post hoc analysis of the ROCAS (Regression of Cerebral Artery Stenosis) study. [22] Subcortical may also be differentiated from cortical VCI and Alzheimer's disease by the absence of aphasia, apraxia, agnosia, amnesia, and hemianopia[48] although cortical and subcortical lesions, with or without Alzheimer's disease, frequently coexist so the specificity of these symptoms will be limited. Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions. [63] Interestingly, type 2 diabetes is associated with a greater increase in depressive symptoms, which SVD may contribute to.[23,64]. Makin SDJ, Doubal FN, Dennis MS, Wardlaw JM. Cleveland Clinic is a non-profit academic medical center. Dementia; Magnetic resonance imaging; Mild cognitive impairment; Risk factors; Small vessel disease; Stroke; Symptoms; Treatment. Liu-Ambrose T, Best JR, Davis JC, Eng JJ, Lee PE, Jacova C, et al. Choi SH, Na DL, Chung CS, Lee KH, Na DG, Adair JC. Finally, we advocate for more clinical trials to identify effective lifestyle and pharmaceutical interventions. [105] In contrast, patients with stroke and severe WMH had less progression of WMH if they were on a statin pre-stroke in the VITATOPS study. 13. Allopurinol, a xanthine oxidase inhibitor, has multiple effects that may be beneficial in SVD. Further work on interactions between SVD, depression, and their confounders will help to clarify the vascular depression hypothesis. SUMMARY: Small vessel disease, a disorder of cerebral microvessels, is an expanding epidemic and a common cause of stroke and dementia. Untreated microvascular ischemic disease can lead to serious, life-threatening complications. Amarenco P, Goldstein LB, Messig M, ONeill BJ, Callahan A III, Sillesen H, et al. 43. SVD often arises on a background of other complex comorbidities, and untangling SVD symptoms from those attributable to other conditions requires careful clinical judgment including neuroimaging review. Chokesuwattanaskul A, Cheungpasitporn W, Thongprayoon C, Vallabhajosyula S, Bathini T, Mao MA, et al. Sakakibara R, Hattori T, Uchiyama T, Yamanishi T. Urinary function in elderly people with and without leukoaraiosis: relation to cognitive and gait function. 75. Eight studies, mostly in older community dwelling-subjects, detected urinary symptom associations with WMH (total n = 1944),[3441] while two did not (n = 648). Clancy, Una1; Appleton, Jason P.2,3; Arteaga, Carmen1; Doubal, Fergus N.1; Bath, Philip M.2,4; Wardlaw, Joanna M.1, 1Centre for Clinical Brain Sciences, and UK Dementia Research Institute, University of Edinburgh, Chancellor's Building, 49 LIttle France Crescent, Edinburgh, EH16 4SP, UK, 2Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham NG5 1PB, UK, 3Stroke, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham B15 2GW, UK.
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