Foundations of Modern Stroke Medicine
Posted in Stroke Series on 7th Nov 2013
At the end of the 20th Century, not only were we much less likely to suffer a premature stroke than at the start of the Century, but also much more likely to receive an accurate diagnosis and effective treatment. This paper attempts to summarise some of the critical British contributions to the advances in stroke prevention and treatment, but does not pretend to be a comprehensive review.
From being a ‘Cinderella disease’ where it was felt that little could be done and patients were sometimes left ‘languishing’ in medical wards, often for months, our main hospitals now have urgent transient ischaemic attack (TIA) clinics, hyper-acute stroke units (providing thrombolytic treatment), and active rehabilitation services.
A greater understanding of the control of the cerebral circulation in health and disease was achieved using newer techniques for measuring cerebral blood flow (CBF). Murray Harper’s1 work improved awareness of cerebral autoregulation, by which blood flow is kept constant, with changing blood pressures (see Figure 1 below, which shows a stable CBF throughout a wide BP range). At very high blood pressure, autoregulation begins to fail and CBF rises, increasing the risks of oedema and haemorrhage. The concept developed that blood vessels in the neighbourhood of a stroke were also damaged and lost the ability to autoregulate. Local CBF then became dependent on blood pressure (the pressure-passive response) and vulnerable to both low and high blood pressures.
The Queen Square CBF group (du Boulay, Marshall, Ross Russell and Symon) was set up following the innovative work of Lassen and Ingvar. The group helped emphasise the role of CO2 in controlling CBF and the influence of high blood viscosity and high hamatocrit in lowering CBF.2 Venesection was shown to have a dramatic effect on increasing CBF even in people with haematocrit levels in the upper normal range.3 Substantial reductions in risk of occlusive vascular events, including stroke, in patients with polycythaemia was achieved by advising the lowering of the target haematocrit from 0.50 to below 0.45,4 thereby halving the whole blood viscosity. However, enthusiasm for using haemodilution to improve CBF after stroke in patients without polycythaemia waned in the UK, when the Queen Square CBF Group went on to show that CBF increased largely due to maintaining oxygen delivery rather than due to lowering viscosity.5 Nevertheless, haemodilution continued to be used for some years elsewhere in Europe and in the USA to increase CBF, reasoning that increasing blood flow to vulnerable areas was beneficial however it was achieved.
The important concept of the ischaemic penumbra, with threatened but still viable cells surrounding a severely ischaemic centre6 and thresholds in cerebral ischaemia was investigated by Lindsay Symon’s group at the Institute of Neurology, Queen Square. This concept underpins the only licensed treatment for acute ischaemic stroke: intravenous thrombolysis. Ischaemic areas lose autoregulation and perfusion can be increased by induced hypertension.7 The potential damaging effect of low blood pressure in the presence of cerebral vasospasm after subarachnoid haemorrhage and the benefits of improving blood flow and cerebral function by raising blood pressure were advocated by them. The syndrome of critical brain perfusion and the clinical recognition and treatment of borderzone (watershed) infarction of the brain were emphasised.8
The importance of transient ischaemic attacks (TIAs) as warnings of impending strokes was highlighted by Acheson and Hutchinson’s natural history paper;9 they emphasised that the vertebral arteries were also important and recommended that they should be routinely examined. Initially TIAs were thought to be due to ‘vasospasm’. Sir George Pickering was one of the first to doubt this.10 Attention turned to a haemodynamic insufficiency with short-lived reductions in blood flow to a vulnerable region provoked by a fall in blood pressure. However, the work of Marshall and Kendell showed that lowering blood pressure led to global syncopal symptoms, rather than to the focal ones typical of TIAs.11
After Miller Fisher’s suggestion that emboli from thrombus in neck vessels might be important, came Ross Russell’s observations of repeated emboli moving through the retinal arteries in patients with carotid stenosis.12 The view that most TIAs were thrombo-embolic in origin was strengthened. Attention then focused on potential sources of cerebral emboli not only from the aorta and other major vessels, especially the carotid bifurcation, but also from the heart. The importance of atrial fibrillation became clearer. The role of paradoxical emboli, especially through the commonly patent foramen ovale (PFO), generated much interest and discussion on the pros and cons of closing the PFO, and the role of transcranial Doppler techniques for detecting ongoing micro-emboli. The significance of platelets in the growth and embolisation of mural thrombus attracted much interest. The use of anti-platelet therapy in reducing thrombo-embolism was stimulated.13
Ross Russell’s work on cerebral microaneurysms14 in the brains of patients with hypertension, and their potential role in cerebral haemorrhage, was a major contribution: renewed interest has been aroused by the demonstration of microbleeds on blood-sensitive MRI, some of which may be associated with microaneurysms.15
The incidence of stroke fell in developed countries from the mid 20th Century, even before effective treatment became available. A similar decline in myocardial infarcts has also occurred. The reasons for this have not been fully explained. Less cigarette smoking has contributed. A controversial suggestion is that the increased availability of refrigeration, both commercially and domestically, substantially reduced the need for salt as a food preservative. This may have had an effect on reducing the prevalence of high blood pressure, the most important remediable risk factor for stroke. The role of infection in increasing the risks of thrombo-embolism, myocardial infarction and stroke and the widespread use of antibiotics possibly reducing these risks also need to be considered.
The Oxford Community Stroke Project16 was set up by Charles Warlow in the 1980’s and it continues to provide useful information, e.g. the proportion of strokes due to cerebral haemorrhage has fallen substantially.17 There are, nevertheless, still approximately 150,000 new strokes in the UK each year. Stroke remains a major cause of death and the main cause of ongoing disability. Prevention remains a top priority.
Since age is the main risk factor for stroke and since the effects of different risk factors are cumulative, it may be more important to treat the elderly than those in younger age groups. This was not appreciated until recently: up to the 1980’s, high blood pressure was often left untreated.
Blood Pressure Treatment
Hypertension used to be considered to be a disease, not just as the upper end of the BP range. It is better regarded as a continuum.18 The BP level at which treatment is recommended has come down and continues to do so. There have been some excellent blood pressure randomised multicentre trials, including the huge ASCOT study coordinated by Peter Sever’s team from St Mary’s Hopsital.19 From advising: ‘just bring the blood pressure down’, management has matured, with the demonstration that different hypotensive agents may have different benefits and disadvantages at different ages and in different racial groups. In patients following stroke, a raised blood pressure was previously often left untreated. Now there is now a substantial body of evidence of benefit from lowering BP to prevent stroke.20
Anticoagulant treatment was effective at preventing thromboses in several clinical situations. So, Marshall, Shaw and Bradford Hill21 performed a very early trial of anticoagulation in TIAs. The results were inconclusive, possibly as a result of small numbers, but also because the ethics of the time ruled that it was unacceptable for the control group to have a placebo. So their controls were given 1mg of warfarin/day, which was then thought to be ineffective. So it was really a trial of ‘normal’ warfarin doses, controlled by INR, versus low dose warfarin; some of the control group might thus have had some anti-thrombotic protection.
The role of platelets in TIAs became a concern in the 1960’s and 1970’s. The UK-TIA Aspirin Trial, at the time the biggest study randomising 3,000 patients failed to show a statistically significant benefit on reducing the risk of stroke in patients presenting with TIAs. This was a stimulus for the introduction of meta-analyses of similar trials.22 Meta-analysis of the aspirin trials available did show a modest benefit in reducing the risk of stroke and myocardial infarction.23 Low dose aspirin seemed as effective as high dose and was somewhat less likely to produce side effects. Increased statistical awareness has improved trial design. The development of the Clinical Trials Service Unit in Oxford and the International Centre for Circulatory Health at St Mary’s, among others, have allowed the UK to coordinate and to participate in several important vascular trials of other anti-platelet agents and fibrinolysis.
Other Preventative Measures
The use of statins has become widespread.24 Statins are now introduced at cholesterol levels which would have gone untreated in previous decades.
The harmful effects of poorly controlled blood glucose levels in diabetics are now better appreciated, with concerns over the risks of larger strokes with higher glucose levels.25 Extensive studies of diabetes management have been carried out by UK clinicians, involved in the largest cohort studies in the world.
Bickerstaff’s monograph26 on ‘Neurological complications of oral contraceptives’ highlighted the potential risks of stroke. The OCP formulations have since been improved and many strokes prevented.
The important work of Richard Doll and Richard Peto on the risks of smoking has done much to reduce the prevalence of smoking in Western Countries and to reduce substantially the risks not only of cancers but also of vascular disease and strokes.27
Carotid Artery Stenosis
In 1954 a team from St Mary’s first reported a carotid artery reconstruction in a successful attempt to prevent TIAs progressing to a stroke.28 This triggered a widespread enthusiasm for carotid endarterectomy. Physicians’ concerns were raised about the number of strokes actually being caused by carotid endarterectomy and the invasive angiography that preceded it. So, in the early 1980’s the European Carotid Surgery Trial29 was started, by Charles Warlow with the same core of collaborators as in the UK TIA Aspirin Trial. In 1991, they reported that in patients with more than 70% stenosis, there was an impressive reduction in the risk of stroke. The results were confirmed by a North American Trial30 coordinated by British born neurologist, Henry Barnett. In addition to clear evidence of efficacy, we now also have a better idea on patient selection.31
These studies triggered two large trials of carotid endarterectomy in asymptomatic patients with tight carotid stenoses: the Stroke Association’s and Medical Research Council’s Asymptomatic Carotid Surgery Trial, ACST32 and the North American ACAS trials. These again showed a benefit with a 50% reduction in the risk of stroke, but the absolute risks in asymptomatic patients are low and the peri-operative risks are not negligible. This has led to a strange polarisation of management advice.Patients seeing surgeons may be advised to have an endarterectomy because by doing so the risk of stoke is significantly reduced. Those seeing a physician may be advised that the absolute risk is low and that best medical treatment should suffice pending any TIAs. There has also been enthusiasm for using carotid angioplasty and stenting instead of endarterectomy. Questions remain. The trials continue. ACST-2 and ECST-2, both UK-led trials, are now recruiting.
Rapid access TIA Clinics
The realisation that the risks of stroke were highest soon after a TIA and that if surgery were delayed the benefit would be lost has led to a change of attitude and the establishment of urgent TIA clinics around the Country, based on evidence in part from the OXVASC study led by Peter Rothwell. The aim is to see patients and to investigate them promptly including with brain scanning and carotid imaging within 24 hours. Rather than being set-up just where local neurologists or physicians were interested, a TIA service became a priority for NHS managers.
Acute Stroke Diagnosis
Perhaps the greatest contribution to stroke diagnosis and management was the Nobel laureate Sir Godfrey Hounsfield’s (see Figure 2), invention of computerised axial tomography.33 Before the CT scan it was difficult to know whether a stroke was due to an infarct or haemorrhage. Now it is possible to detect significant amounts of acute cerebral haemorrhage within minutes.
As well as permitting anatomical localisation, images of the major arteries are possible and thrombolytic treatment can be given promptly. Thrombolytic treatment had been tried in the late 60’s and early 70’s,but was abandoned because of fatal haemorrhages – usually in those patients whose stroke had in fact been a haemorrhage, but diagnosed as an infarct (Thomas DJ,personal observations). See Figure 3 of a CT brain scan showing a recent cerebral haemorrhage, a clear contraindication to thrombolytic therapy.
Diagnosis was further improved by extending the X-ray computerised tomography techniques to nuclear magnetic resonance imaging, for which Sir Peter Mansfield (see Figure 4), also won a Nobel prize.34 ‘Nuclear’ was dropped to avoid confusion with ionising radiation. The development of different MR sequences including diffusion-weighted imaging and MR angiography have transformed our assessment and understanding of stroke and have helped improve management. See Figure 5, a diffusion weighted image (DWI) MRI scan showing a recent small subcortical cerebral infarct. An under-emphasised advantage of early brain imaging is that it prevents patients with non-stroke conditions, masquerading as a stroke (“mimics”), receiving inappropriate treatment.
Acute Stroke Treatment
It came as a surprise that even before any apparently effective treatments became available, patients in units dedicated to stroke care did better than those on general wards.35 This was not an isolated finding. The reasons are not immediately apparent. Was it just the MDT approach with the concentration of interested medical, nursing and physical therapy staff? Certainly awareness of swallowing difficulties and improved care of the airway helped prevent aspiration problems and undernutrition and dehydration. Hospital trusts became really motivated to provide stroke units only after thrombolytic therapy was accepted to be effective and the number of acute units greatly increased. Many hospitals now have hyper-acute units for the first few days with patients moving-on to stroke rehabilitation areas. Lengths of hospital stay have been reduced substantially, and outcomes seem to be improved. The Royal College of Physicians’ national sentinel audit for stroke has raised standards and significantly improved stroke care.36 With a motivated, well-coordinated ambulance service and increased patient and relative awareness, some hospitals are now able to offer thrombolytic treatment to up to 30% of their cases.
Other Acute Treatments
In contrast to the success of thrombolytic treatment,37 neuroprotective agents have been disappointing.38 Anticoagulants may have a role (as yet unproven) but only in carefully selected patients.39 Antiplatelet agents are worth introducing as a secondary prevention after acute stroke to reduce the risk of a recurrent stroke, but the number needed to treat is high.40 The need to control glucose levels may not be sufficiently addressed. The use of glucose, potassium and insulin infusions were tried again, after a 30 year interval.25
Most of what has been said so far has referred to cerebral infarction. Although some of the same risk factors are involved and rehabilitation may be similar, the acute management of cerebral haemorrhage is quite different. Sir Wylie McKissock, the influential neurosurgeon at Atkinson Morley’s Hospital and Queen Square, tested the effect of removing intracranial haematomas in stroke patients. His results were somewhat discouraging.41 So surgery, with the exception of that for acute cerebellar haemorrhages was largely abandoned in the UK until David Mendelow and his colleagues re-addressed the question. With better modern anaesthetic and post-operative care and less invasive surgery, a multicentre trial was set-up (STICH). Again the results have been discouraging, failing to show overall benefit from surgical evacuation.42 However, trials of acute blood pressure lowering in cerebral haemorrhage have been promising, and a large UK-led trial of tranexamic acid is underway.
There have been significant advances with fewer open operations, more endovascular procedures and better measures to recognise and control the effects of cerebral vasospasm and maintain cerebral blood flow. Calcium antagonists have been used.43 Treatment of hydrocephalus has been improved.44
Rehabilitation results are improved after good acute care, which has minimised the volume of brain damage and has prevented pressure sores, venous thromboses, shoulder subluxation and contractures which all make therapy more difficult.
Therapy can begin in the acute unit, particularly with correct positioning, swallowing assessments, protection of the airway and maintaining nutrition. A goal-orientated approach with a skilled MDT is now widely recommended. The days of not emphasising speech therapy because it was little better than ‘just talking to the patient’ and not offering a place in rehabilitation to those with marked proprioceptive problems or even a field defect with inattention are happily past. Modern MRI with functional imaging may help with prognosis, predicting and planning brain recovery. The need to recognise those with dementia and other cognitive problems is now better appreciated when rehabilitation is being considered. A substantial number of patients suffer post-stroke depression. This needs to be recognised. It is often amenable to treatment, improving quality of life and motivation.45
The Royal College of Physicians36 has had an important role in improving stroke services around the UK; the college stroke audit highlighted deficiencies, and managers were motivated to rectify them. The monitoring looks likely to continue. There is no place for complacency. The Stroke Association’s survey of patients and carers found that a major criticism was that they felt abandoned on returning home from hospital. There was a sudden lack of medical and nursing care and a dramatic drop in therapy. This separation of hospital and community services needs to be addressed. This problem is not confined to the United Kingdom. In addition, it is disappointing that health and social services remain separated in the UK.
The NHS provides a unique opportunity for translational research, stimulating the creation of the National Institute for Health Research (NIHR) and Stroke Research Network, which has dramatically increased participation of stroke patients in research studies (from about 2,000 per year in 2005 to over 12,000 per year in 2012), which should continue to have have far-reaching beneficial effects.
In the UK, neurologists have been slower to take on the management of the hyper-acute stroke units in the same way as their European and North American colleagues. Hopefully this will be rectified by improvements in the UK training programmes to allow stroke (and all of the acute neurological conditions that can mimic it) to play the central role it deserves in the training of UK neurologists, thus stimulating continued advances in this exciting field.
1.Harper AM. Autoregulation of cerebral blood flow: influence of the arterial blood pressure on the blood flow through the cerebral cortex. J Neurol Neurosurg Psychiat 1966;29:398-403.
2.Thomas DJ, du Boulay GH, Marshall J, Pearson TC, Ross Russell RW, Symon L, Wetherley-Mein G, Zilkha E. Cerebral blood-flow in polycythaemia. Lancet 1977;2:161-3.
3.Thomas DJ, du Boulay GH, Marshall J, Pearson TC, Ross Russell RW, Symon L, Wetherley-Mein G, Zilkha E. Effect of haematocrit on cerebral blood-flow in man. Lancet 1977;2:941-3.
4.Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 1978;2:1219-22.
5.Wade JP. Transport of oxygen to the brain in patients with elevated haematocrit values before and after venesection. Brain;106:513-23.
6.Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischaemia-the ischaemic penumbra. Stroke 1981;12:723-5.
7.Symon L, Branston NM, Strong AJ. Autoregulation in acute focal ischaemia. An experimental study. Stroke 1976;7:547-54.
8.Ross Russell RW, Page NGR. Critical perfusion of the brain and retina. Brain 1983;106:419-34.
9.Acheson J, Hutchinson EC. The natural history of ‘focal cerebral vascular disease’. Q J Med 1971;40:15-23.
10.Pickering GW. Transient cerebral paralysis with hypertension and with cerebral embolism. J Amer.med Ass 1948;137:423-30.
11. Kendell RE, Marshall J. Role of hypotension in the genesis of transient focal cerebral ischaemic attacks. Brit med J 1963;2:344-8.
12.Ross Russell RW. Observations on the retinal blood-vessels in monocular blindness. Lancet 1961;2:1422-8.
13.Harrison MJG, Marshall J, Meadows JC, Ross Russell RW. Effect of aspirin in amaurosis fugax. Lancet 1971;2:743-4.
14.Ross Russell RW. Observations on intracranial aneurysms. Brain 1963;86:425-42.
15.Charidimou A, Kakar P, Fox Z, Werring DJ. Cerebral microbleeds and recurrent stroke risk. Stroke 2013;44:995-1001.
16.Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade DT, Warlow CP. Long-term survival after first ever stroke;the Oxfordshire Community Stroke Project. Stroke 1993;24:796-800.
17.Lovelock CE, Molyneux AJ, Rothwell PM. Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK beteen 1981 and 2006 a population-based study. Lancet Neurol 2007;6:487-93.
18.Pickering GW. Normotension and hypertension:the mysterious viability of the false. Am J Med 1978;65:561.
19.Dahlof B, Sever PS, Poulter NR, et al for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethazide as required in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm(ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895-906.
20.Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary prevention of stroke and other vascular events:a systematic review. Stroke 2003;34:2741-8.
21.Hill AB, Marshall J, Shaw DA. A controlled trial of long-term anticoagulant therapy in cerebrovascular disease. Quart J Med 1960;29:597-609.
22.Peto R, Collins R, Gray R. Large-scale randomised evidence: large, simple trials and overviews of trials. J clin Epidemiol 1995;48:23-40.
23.Antiplatelet Trialists’ Collaboration. Secondary prevention collaborative overview of randomised trials of antiplatelet therapy. I.Prevention of death,myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994;308:81-106.
24.Cholesterol Treatment Trialists’ Collaborators (CTT). Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 09,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
25.Scott JF, Robinson GM, French JM, O’connell JE, Alberti KGMM, Gray CS. Glucose potassium insulin infusions in the treatment of acute stroke patients with mild to moderate hyperglycaemia. Stroke 1999;30:793-9.
26.Bickerstaff ER. Neurological complications of oral contraceptives. Oxford University Press 1975.
27.Peto R. Smoking and death: the past 40 years and the next 40. Br Med J 1994;309:937-9.
28.Eastcott HHG, Pickering GW, Robb CG. Reconstruction of the internal carotid artery in a patient with intermittent attacks of hemiplegia. Lancet 1954;2:994-6.
29.European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. Lancet 1991;337:1235-43.
30.North American Symptomatic Carotid Surgery Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Eng J Med 1991;325:445-53.
31.Rothwell P, Warlow CP on behalf of the European Carotid Surgery Trialists’ Collaborative Group. Prediction of benefit from carotid endarterectomy in individual patients. Lancet 1999;353:2105-10.
32.MRC Asymptomatic Carotid Surgery Trial Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms:randomised controlled trial. Lancet 2004;363:1491-502.
33.Hounsfield GN. Computerised transverse axial scanning(tomography):1.Description of system. Br J Radiol 1973:46:1016-22.
34.Mansfield P, Maudsley AA. Medical imaging by NMR. Br J Radiol 1977;50:188-94.
35.Langhorne P, Williams BO, Gilchrist W, Howie K. Do stroke units save lives? Lancet 1993;342;395-8.
36.Rudd AG, Irwin P, Rutledge Z et al. The national sentinel audit for stroke:a tool for raising standards of care. J R Coll Physicians 1999;33:460-4.
37.Wardlaw JM, Warlow CP, Counsell C. Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke. Lancet 1997;350:607-14.
38.Dorman PJ, Counsell CE, Sandercock PAG. Recently developed neuroprotective therapies for acute stroke. CNS Drugs 1996;5:457-74.
39.Sandercock P, Mielke O, Liu M et al. Anticoagulants for preventing recurrence following presumed non-cardio-embolic ischaemic stroke or transient ischaemic attack. Cochrane Database Syst Rev 2003;1:CD000248.
40.Chen ZM, Sandercock P, Pan HC et al. On behalf of the CAST & IST collaborative groups.Indications for aspirin use in acute ischaemic stroke:a combined analysis of 40,000 randomised patients from the Chinese Acute Stroke Trial and the International Stroke Trial. Stroke 2000;31:1240-9.
41.McKissock W, Richardson A, Taylor J. Primary intracerebral haemorrhage:a controlled trial of surgical and conservative therapy in 180 selected cases. Lancet 1961;2:221-6.
42.Mendelow AD, Gregson BA, Fernandes HM et al. Early surgery versus initial conservative treatment in patients with spontaneous supra-tentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage(STICH):a randomised trial. Lancet 2005;365:387-97.
43.Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. Br Med J 1989;298:636-42.
44.Pickard JD. Early post-haemorrhagic hydrocephalus. Br Med J 1984;289:569-70.
45.House A, Dennis M, Hawton K, Warlow CP. Methods of identifying mood disorders in stroke patients:experience in the Oxfordshire Community Stroke Project. Age Ageing 1989;18:371-9.
ACNR2013:13:6. Published online 8/11/13
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