Epidemiology
There are more than 100,000 strokes in the UK each year causing 38,000 deaths, making it a leading cause of death and disability.[5]National Institute of Health and Care Excellence. NICEimpact: stroke. May 2019 [internet publication].
https://www.nice.org.uk/Media/Default/About/what-we-do/Into-practice/measuring-uptake/NICE-Impact-stroke.pdf
[6]Royal College of Physicians. Sentinel Stroke National Audit Programme (SSNAP). Is stroke care improving? The second SSNAP annual report. December 2015 [internet publication].
https://www.hqip.org.uk/resource/is-stroke-care-improving-the-second-ssnap-annual-report/
[7]Stroke Association. State of the nation: stroke statistics. January 2017 [internet publication].
https://www.stroke.org.uk/sites/default/files/state_of_the_nation_2017_final_1.pdf
People are most likely to have a stroke over the age of 55.[8]Wang Y, Rudd AG, Wolfe CD. Age and ethnic disparities in incidence of stroke over time: the South London Stroke Register. Stroke. 2013 Dec;44(12):3298-304.
https://www.doi.org/10.1161/STROKEAHA.113.002604
http://www.ncbi.nlm.nih.gov/pubmed/24114452?tool=bestpractice.com
[7]Stroke Association. State of the nation: stroke statistics. January 2017 [internet publication].
https://www.stroke.org.uk/sites/default/files/state_of_the_nation_2017_final_1.pdf
Stroke is the third leading cause of death and a major cause of disability in the US, and the third leading cause of death in Canada.[9]Wolfe C. The burden of stroke. In: Wolfe C, Rudd T, Beech R, eds. Stroke services and research. London, UK: The Stroke Association; 1996.[10]Statistics Canada. The 10 leading causes of death, 2013. Mar 2017 [internet publication].
https://www150.statcan.gc.ca/n1/pub/82-625-x/2017001/article/14776-eng.htm
Ischaemic stroke prevalence can be further sub-divided according to pathophysiological mechanism: extracranial atherosclerosis (10%), intracranial atherosclerosis (10%), cardioembolic (25%), lacunar infarction ([small vessel disease] 15%), indeterminate aetiology ([i.e., cryptogenic] 30%), or other defined causes (10%). Ischaemic stroke is more common in older people, people with lower levels of education, and African-American or Hispanic people.[11]Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics - 2018 update: a report from the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-492.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000558
http://www.ncbi.nlm.nih.gov/pubmed/29386200?tool=bestpractice.com
The overall incidence of stroke as well as stroke mortality has been decreasing over the last few decades; this is thought to be driven by improvements in stroke care.[12]Seminog OO, Scarborough P, Wright FL, et al. Determinants of the decline in mortality from acute stroke in England: linked national database study of 795 869 adults. BMJ. 2019 May 22;365:l1778.
https://www.doi.org/10.1136/bmj.l1778
http://www.ncbi.nlm.nih.gov/pubmed/31122927?tool=bestpractice.com
Risk factors
Even after controlling for other age-related conditions such as hypertension, this remains a strong non-modifiable risk factor.[11]Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics - 2018 update: a report from the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-492.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000558
http://www.ncbi.nlm.nih.gov/pubmed/29386200?tool=bestpractice.com
Stroke-causing genetic disorders with mendelian inheritance are rare. However, twin studies show that a significant portion of stroke risk is heritable, and epidemiological studies show that family history of stroke is a risk factor.[14]Flossmann E, Schulz UG, Rothwell PM. Systematic review of methods and results of studies of the genetic epidemiology of ischemic stroke. Stroke. 2004 Jan;35(1):212-27.
https://www.ahajournals.org/doi/full/10.1161/01.str.0000107187.84390.aa
http://www.ncbi.nlm.nih.gov/pubmed/14684773?tool=bestpractice.com
Numerous candidate genes have been proposed, but none have yet been consistently replicated as a strong risk factor for stroke.[15]Rosand J, Bayley N, Rost N, et al. Many hypotheses but no replication for the association between PDE4D and stroke. Nat Genet. 2006 Oct;38(10):1091-2.
http://www.ncbi.nlm.nih.gov/pubmed/17006457?tool=bestpractice.com
History of previous ischaemic stroke indicates that the patient may sustain more ischaemic strokes in the future (particularly if risk factors, e.g., hypertension, are not corrected).
Strongly associated with increased incidence of ischaemic stroke.[16]Kannel WB, Wolf PA, Verter J, et al. Epidemiologic assessment of the role of blood pressure in stroke: the Framingham study. JAMA. 1970 Oct 12;214(2):301-10.
http://www.ncbi.nlm.nih.gov/pubmed/5469068?tool=bestpractice.com
Strongly associated with increased incidence of ischaemic stroke.[17]Wolf PA, D'Agostino RB, Kannel WB, et al. Cigarette smoking as a risk factor for stroke: the Framingham study. JAMA. 1988 Feb 19;259(7):1025-9.
http://www.ncbi.nlm.nih.gov/pubmed/3339799?tool=bestpractice.com
Strongly associated with increased incidence of ischaemic stroke.[18]Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham study. JAMA. 1979 May 11;241(19):2035-8.
http://www.ncbi.nlm.nih.gov/pubmed/430798?tool=bestpractice.com
Strongly implicated in the risk of cardioembolic stroke but not other ischaemic stroke sub-types.[19]Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke. 1991 Aug;22(8):983-8.
http://www.ncbi.nlm.nih.gov/pubmed/1866765?tool=bestpractice.com
Several other cardiac conditions have been reported as potential causes of cardioembolism, with varying degrees of evidence. These conditions include myocardial infarction with regional wall motion abnormalities or decreased left ventricular ejection fraction, valvular disease, patent foramen ovale with or without atrial septal aneurysm, mitral valve prolapse, prosthetic heart valve, and cardiomyopathy.[20]Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke. 2001 Jan;32(1):280-99.
https://www.ahajournals.org/doi/10.1161/01.STR.32.1.280
http://www.ncbi.nlm.nih.gov/pubmed/11136952?tool=bestpractice.com
Modestly associated with risk of first ever ipsilateral ischaemic stroke and strongly associated with stroke recurrence after ipsilateral ischaemic stroke.[21]Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med. 1986 Oct 2;315(14):860-5.
http://www.ncbi.nlm.nih.gov/pubmed/3528855?tool=bestpractice.com
[22]Barnett HJ, Taylor DW, Haynes RB, et al; North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991 Aug 15;325(7):445-53.
https://www.nejm.org/doi/10.1056/NEJM199108153250701
http://www.ncbi.nlm.nih.gov/pubmed/1852179?tool=bestpractice.com
Degree of stenosis is related to the risk of recurrent stroke.[23]Barnett HJ, Taylor DW, Eliasziw M, et al; North American Symptomatic Carotid Endarterectomy Trial Collaborators. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998 Nov 12;339(20):1415-25.
https://www.nejm.org/doi/10.1056/NEJM199811123392002
http://www.ncbi.nlm.nih.gov/pubmed/9811916?tool=bestpractice.com
Associated with vascular stenosis, brain ischaemia, and Moyamoya disease (vascular occlusion affecting circle of Willis). In children, prophylactic transfusion based on transcranial Doppler ultrasound criteria has been shown to lower subsequent stroke risk.[24]Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998 Jul 2;339(1):5-11.
https://www.nejm.org/doi/10.1056/NEJM199807023390102
http://www.ncbi.nlm.nih.gov/pubmed/9647873?tool=bestpractice.com
Large prospective studies have shown that increased serum total cholesterol is modestly associated with an increased risk of ischaemic stroke.[25]Iso H, Jacobs DR Jr, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989 Apr 6;320(14):904-10.
http://www.ncbi.nlm.nih.gov/pubmed/2619783?tool=bestpractice.com
There are few studies on the association of low-density lipoprotein cholesterol with stroke, and the results are conflicting.[20]Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke. 2001 Jan;32(1):280-99.
https://www.ahajournals.org/doi/10.1161/01.STR.32.1.280
http://www.ncbi.nlm.nih.gov/pubmed/11136952?tool=bestpractice.com
A meta-analysis showed that increased high-density lipoprotein is protective against ischaemic stroke.[26]Amarenco P, Labreuche J, Touboul PJ. High-density lipoprotein-cholesterol and risk of stroke and carotid atherosclerosis: a systematic review. Atherosclerosis. 2008 Feb;196(2):489-96.
http://www.ncbi.nlm.nih.gov/pubmed/17923134?tool=bestpractice.com
Stroke symptoms are more likely among those with lower income and lower educational attainment.[11]Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics - 2018 update: a report from the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-492.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000558
http://www.ncbi.nlm.nih.gov/pubmed/29386200?tool=bestpractice.com
Have been associated with increased incidence of ischaemic stroke.[11]Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics - 2018 update: a report from the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-492.
https://www.ahajournals.org/doi/full/10.1161/CIR.0000000000000558
http://www.ncbi.nlm.nih.gov/pubmed/29386200?tool=bestpractice.com
[27]Broderick J, Brott T, Kothari R, et al. The Greater Cincinnati/Northern Kentucky Stroke Study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998 Feb;29(2):415-21.
https://www.ahajournals.org/doi/full/10.1161/01.str.29.2.415
http://www.ncbi.nlm.nih.gov/pubmed/9472883?tool=bestpractice.com
[28]Oshunbade AA, Yimer WK, Valle KA, et al. Cigarette smoking and incident stroke in blacks of the Jackson Heart Study. J Am Heart Assoc. 2020 Jun 16;9(12):e014990.
https://www.doi.org/10.1161/JAHA.119.014990
http://www.ncbi.nlm.nih.gov/pubmed/32517526?tool=bestpractice.com
Some, but not all, of this increased risk is accounted for by higher prevalence of known vascular risk factors such as hypertension and diabetes.
Epidemiological studies show a relationship between decreased stroke risk and increased consumption of fruits and vegetables,[29]Bazzano LA, Serdula MK, Liu S. Dietary intake of fruits and vegetables and risk of cardiovascular disease. Curr Atheroscler Rep. 2003 Nov;5(6):492-9.
http://www.ncbi.nlm.nih.gov/pubmed/14525683?tool=bestpractice.com
decreased consumption of sodium,[30]He J, Ogden LG, Vupputuri S, et al. Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults. JAMA. 1999 Dec 1;282(21):2027-34.
https://jamanetwork.com/journals/jama/fullarticle/192154
http://www.ncbi.nlm.nih.gov/pubmed/10591385?tool=bestpractice.com
and increased consumption of potassium.[31]Khaw KT, Barrett-Connor E. Dietary potassium and stroke-associated mortality: a 12-year prospective population study. N Engl J Med. 1987 Jan 29;316(5):235-40.
http://www.ncbi.nlm.nih.gov/pubmed/3796701?tool=bestpractice.com
The effects of decreased sodium and increased potassium intake may be mediated by a lower risk of hypertension.
Decreased physical activity has been associated with increased risk of ischaemic stroke.[32]Sacco RL, Gan R, Boden-Albala B, et al. Leisure-time physical activity and ischemic stroke risk: the Northern Manhattan stroke study. Stroke. 1998 Feb;29(2):380-7.
https://www.ahajournals.org/doi/full/10.1161/01.str.29.2.380
http://www.ncbi.nlm.nih.gov/pubmed/9472878?tool=bestpractice.com
Overweight and obese people have a modestly increased risk of ischaemic stroke.[33]Kurth T, Gaziano JM, Rexrode KM, et al. Prospective study of body mass index and risk of stroke in apparently healthy women. Circulation. 2005 Apr 19;111(15):1992-8.
https://www.ahajournals.org/doi/full/10.1161/01.cir.0000161822.83163.b6
http://www.ncbi.nlm.nih.gov/pubmed/15837954?tool=bestpractice.com
[34]Kurth T, Gaziano JM, Berger K, et al. Body mass index and the risk of stroke in men. Arch Intern Med. 2002 Dec 9-23;162(22):2557-62.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/754810
http://www.ncbi.nlm.nih.gov/pubmed/12456227?tool=bestpractice.com
Heavy alcohol use is associated with an increased risk of ischaemic stroke.[35]Reynolds K, Lewis B, Nolen JD, et al. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003 Feb 5;289(5):579-88.
http://www.ncbi.nlm.nih.gov/pubmed/12578491?tool=bestpractice.com
Light to moderate alcohol consumption may be protective against ischaemic stroke.[35]Reynolds K, Lewis B, Nolen JD, et al. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003 Feb 5;289(5):579-88.
http://www.ncbi.nlm.nih.gov/pubmed/12578491?tool=bestpractice.com
A small increased risk of ischaemic stroke may be present in users of oral contraceptive pills; however, studies are conflicting.[36]Gillum LA, Mamidipudi SK, Johnston SC. Ischemic stroke risk with oral contraceptives: a meta-analysis. JAMA. 2000 Jul 5;284(1):72-8.
http://www.ncbi.nlm.nih.gov/pubmed/10872016?tool=bestpractice.com
Clinical trials of oestrogen or oestrogen plus progestogen in post-menopausal women have shown an increased incidence of ischaemic stroke.[37]Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al. Effects of conjugated equine estrogen on stroke in the Women's Health Initiative. Circulation. 2006 May 23;113(20):2425-34.
https://www.ahajournals.org/doi/full/10.1161/circulationaha.105.594077
http://www.ncbi.nlm.nih.gov/pubmed/16702472?tool=bestpractice.com
[38]Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33.
https://jamanetwork.com/journals/jama/fullarticle/195120
http://www.ncbi.nlm.nih.gov/pubmed/12117397?tool=bestpractice.com
Several drugs may influence stroke risk. Cocaine and other drugs may cause changes in blood pressure or vasculitic-type changes in the intracranial circulation.
Unsafe intravenous injections may lead to infective endocarditis with subsequent cardioembolism, or paradoxical embolism of injected foreign material.
Case-control studies show an elevated risk of stroke associated with migraine, particularly in younger women and in those with migraine with aura.[39]Kurth T, Slomke MA, Kase CS, et al. Migraine, headache, and the risk of stroke in women: a prospective study. Neurology. 2005 Mar 22;64(6):1020-6.
http://www.ncbi.nlm.nih.gov/pubmed/15781820?tool=bestpractice.com
Prospective and case-control studies show that higher serum homocysteine levels are associated with a higher risk of ischaemic stroke. However, a randomised trial of homocysteine lowering to prevent stroke showed no benefit of therapy.[40]Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004 Feb 4;291(5):565-75.
https://jamanetwork.com/journals/jama/fullarticle/198139
http://www.ncbi.nlm.nih.gov/pubmed/14762035?tool=bestpractice.com
Subsequent studies with stroke as a secondary endpoint have shown varying results.[41]Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77.
https://www.nejm.org/doi/full/10.1056/NEJMoa060900
http://www.ncbi.nlm.nih.gov/pubmed/16531613?tool=bestpractice.com
[42]Bønaa KH, Njølstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006 Apr 13;354(15):1578-88.
https://www.nejm.org/doi/full/10.1056/NEJMoa055227
http://www.ncbi.nlm.nih.gov/pubmed/16531614?tool=bestpractice.com
Therefore, although homocysteine is clearly a marker of ischaemic stroke risk, it remains unclear whether homocysteine itself causes stroke.
Most studies of lipoprotein(a) and ischaemic stroke show increased risk with higher lipoprotein(a) levels. Lipoprotein(a) levels can be lowered with niacin, but it is not known whether lipoprotein(a) reduction reduces the risk of ischaemic stroke.
Elevated anti-cardiolipin or anti-beta2-glycoprotein-1 antibody levels have been associated with stroke.
Hereditary conditions associated with venous thromboembolism (e.g., antithrombin III deficiency, protein C deficiency, protein S deficiency, factor V Leiden mutation, or prothrombin gene mutations) have not been found to be risk factors for ischaemic stroke[20]Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke. 2001 Jan;32(1):280-99.
https://www.ahajournals.org/doi/10.1161/01.STR.32.1.280
http://www.ncbi.nlm.nih.gov/pubmed/11136952?tool=bestpractice.com
but are related to the risk of cerebral venous sinus thrombosis.
The possibility that hypercoagulable states may be more strongly associated with certain stroke sub-groups, including stroke in young people, is plausible but has not been evaluated in large studies.
Associated with an increased risk of stroke after controlling for other risk factors.[43]Kuo HK, Yen CJ, Chang CH, et al. Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis. Lancet Neurol. 2005 Jun;4(6):371-80.
http://www.ncbi.nlm.nih.gov/pubmed/15907742?tool=bestpractice.com
Whether it directly causes stroke or is merely a marker of risk is uncertain.
Aortic arch plaques may be a risk factor for recurrent stroke and death. In cases of cryptogenic strokes, further diagnostic tests are warranted to search for large aortic plaques.[44]Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation. 2009 May 5;119(17):2376-82.
https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.108.811935
http://www.ncbi.nlm.nih.gov/pubmed/19380621?tool=bestpractice.com