Getting to know more about stroke, particularly on treatment, recent advances, and future prospects.
STROKE is a common cause of adult disability and the second most common cause of death worldwide after coronary heart disease. The proportion of deaths caused by stroke is 10% to 12% in Western countries while 12% of these events occur in those under 65 years of age.
In the year 2002, stroke was the sixth largest cause of disability. This is measured by reduced disability-adjusted life-years (DALYs); in short, this scale is a measure of the number of years lost prematurely and the number of years lived in disability.
Stroke is also responsible for 9% of all deaths worldwide. In Western societies, it is estimated that stroke will be the fourth most important cause of reduced DALYs.
Stroke also consumes an estimated 2% to 4% of total healthcare costs worldwide.
Incidence of stroke
From medical literature, there exists significant differences in stroke mortality between developed countries. Geographical variations are evident. While the average stroke mortality adjusted for average age showed a figure of 50 to100 per 100,000 people per year, the Russian Federation had a stroke mortality of more than 180 per 100,000 people per year and Canada has a figure less than 15 per 100,000. These differences may suggest a role for different frequencies of risk factors such as diabetes, hypertension, alcohol use, dyslipidemia, and smoking.
Other possible contributory factors for such differences include genetic factors and differences in the management of stroke.
In developed countries, there is evidence of a constant reduction in stroke mortality in the last 50 years. The rate of decline was 1% per year until the 1960s, when a more steep fall of 5% per year occurred. However, the trend in developing countries has been limited by the lack of data.
In developed countries, the decline of stroke mortality has been due to better control of traditional stroke risk factors such hypertension, smoking and diabetes. In addition, the general improvement in living standards also contributed. The lessons learnt for developing countries is clear.
In a community-based study in Oxford, England, the incidence of cerebrovascular events (strokes or the occurrence of mini-strokes/near-strokes was observed to be higher than heart disease or peripheral arterial disease or arterial disease affecting the lower part of the body. Stroke incidence (the rate of new strokes occurring over a definite period in time compared against the population under consideration) also varies across Europe. The incidence varies from 240 per 100,000 to 600 per 100,000, again implicating environmental and genetic factors.
A possible explanation for the above findings are methodological problems in the studies. But, on the other hand, a study in Australia also saw similar reductions in stroke incidence of 25% from the year 1989 to 1995. These reductions may be the result of improved risk factor management. In contrast, within a similar time frame, ie from 1987 to 1994, the incidence of stroke increased.
The issue of stroke prevalence or the number of patients affected with stroke at a specific point in time within an examined population has not been studied as well. It reflects the burden of disease in the community but is harder to study as it involves individually identifying such patients in a specific community. Prevalence can also be estimated with knowledge from stroke incidence and mortality as it is roughly equivalent to the number of stroke survivors.
What an increasing prevalence of stroke translates to is the fact that there will be increasing numbers of stroke survivors with decreasing stroke mortality rates. A larger number of stroke survivors will place an increasing burden on healthcare and social care systems.
Symptoms and risk factors
While members of the public are well aware of heart attack symptoms such as sudden onset of chest pain, breathlessness, and sweating, they are not so aware that patients suffering from a stroke or “brain attack” may experience sudden numbness or weakness of the face, arm, or leg, especially on one side of the body, sudden confusion with trouble speaking or understanding, and trouble walking due to loss of balance or incoordination.
As most of these episodes are painless, it is one of the reasons why medical evaluation and treatment is often delayed in strokes.
Overall, strokes are the result of symptoms and signs from a number of possible underlying disease processes or simplistically “causes”. These factors need to be identified and the mechanisms understood in order to minimise brain damage in the early phase of stroke and to prevent recurrence.
The public should be aware that stroke by itself is not a complete diagnosis without understanding the mechanism. This is important to prevent recurrence and to institute proper therapy.
The public should also be aware of the important concept of stroke risk factors. The presence of these medical problems puts the patient at greater risk compared to the normal population. This can be broadly classified as modifiable or non-modifiable. Age and gender are examples of non-modifiable risk factors. Modifiable risk factors such as diabetes, hypertension, high blood lipids, and smoking are common and offer ample opportunities to alter stroke risk in large populations. This fact should be emphasised time and time again.
Other less common risk factors for stroke, such as atrial fibrillation (abnormal, irregular heart rhythm) and transient ischaemic attacks (mini-strokes or near strokes with complete recovery) are also important.
Interestingly, the above risk factors or traditional risk factors can explain only 60% of strokes. On the other hand, these identifiable risk factors can elucidate up to 90% of coronary heart disease. Research is ongoing to explain the 30% difference between strokes and heart disease. Some of these unexplained risk factors may be genetic or as yet undiscovered.
Subtypes and mechanisms of stroke
Stroke or “brain attack” can be divided into two types, ischaemic and haemorrhagic. In ischaemic stroke, blood clots block a blood vessel supplying the brain, leading to death of the related brain cells. In haemorrhagic stroke, a blood vessel breaks or ruptures and the bleeding results in a large blood clot which causes brain cells to die due to the increased pressure.
A good way to remember the different types of stroke is the fact that ischaemic stroke is essentially a “white stroke” as no blood gets to the area of the brain that is affected. Conversely, a haemorrhagic stroke or intracerebral haemorrhage produces a “red stroke”, which describes blood in the brain substance. This analogy helps me explain to patients and their families what a stroke is and what is happening in the brain.
The white and red strokes can be easily distinguished with the introduction of CT (computed tomography) or MR (magnetic resonance) imaging. A CT scan of the brain has been the main investigation of stroke for the last 20 years but MRI has now become more practical and useful as the brain can be scanned in more detail with this method.
Ischaemic strokes or white strokes can be further classified. These classifications were driven by clinical trials of medications tested for this kind of stroke as well as epidemiological or population studies.
The first is the TOAST criteria, which is the conclusion derived from examining the patient neurologically and from the results of important investigations. TOAST criteria identifies the most probable mechanism.
The knowledge of stroke mechanism is important for acute treatment and prevention. The Oxfordshire Community Stroke Project (OCSP) criteria is an older classification based on neurological examination alone and can be applied more widely. The OCSP criteria gives information on outcome. However, it is less accurate in terms of stroke mechanism. While these classifications are useful, they are likely to be revised in the near future on the basis of improved knowledge based on scanning techniques and other advanced investigations.
Ischaemic stroke and transient ischaemic attacks
80% of all strokes are ischaemic or “white” and should be distinguished between events that last 24 hours or less. If the event is less than 24 hours but with full recovery, it is termed a transient ischaemic attack (TIA). It is essentially a mini-stroke or near stroke.
However, with MRI scans, 25% of TIA patients have evidence of tissue damage although neurological examination was normal. Overall, the take home message is transient ischaemic attacks are emergencies and not “mini” problems and should trigger appropriate responses. Important features to help assess the risk of TIAs recurring are age, blood pressure, clinical features, and duration of symptoms.
Types of brain haemorrhage
There are three main types of cerebral bleeding or haemorrhage. The first is called hypertensive small vessel disease where small lipohyalinotic aneurysms (or weakness in the small blood vessels) rupture and bleeding occurs. Approximately two-thirds of patients with this type of brain bleeding have pre-existing or newly diagnosed hypertension.
Other patients may have abnormal structural findings such as tangles of abnormal vessels called vascular malformations or a special type of blood vessel degeneration which involves a biological derivative called amyloid. Subarachnoid haemorrhage is another type of haemorrhage caused by rupture (from weakness) of arterial vascular walls or outpouchings. The collection of blood collects below the inner lining of the brain and acts as a severe irritant.
A variant of subarachnoid haemorrhage is called perimesencephalic haemorrhages, thought to be caused by rupture of veins around the brain.
Outcome of stroke
The outcome from stroke is as follows: 25% of patients are dead within one month, 33% are dead by six months while 50% are dead within a year. These statistics are for ischaemic or “white” strokes.
Intracerebral haemorrhages have a poorer outcome with a one month mortality approaching 50% in most studies.
The main cause of death after a stroke is neurological and a direct effect of the stroke itself. Other contributory causes to early death after a stroke are infections secondary to aspiration of secretions. Subsequent causes of death are related to cardiac disease or related to longer term complications of the stroke.
Stroke recovery in patients can be predicted by the initial early neurological deficit on examination and from the age of the patient. Other factors going together with a poorer outcome include high blood glucose levels, fever, and a previous stroke.
In patients with intracerebral haemorrhage, 33% of patients suffer from a further rapid expansion of the haematoma within the first few hours of onset of the stroke and this factor is related to a poorer outcome at three months after the stroke. Other factors that predict a negative outcome are age and the first neurological deficits at examination.
Ischaemic penumbra and cascade
Another important neurological concept is that of the ischaemic penumbra and cascade. In the setting of large vessel occlusion, there is a part of the brain that is affected functionally from the hypoxia or lack of blood supply but is still viable. This ischaemic penumbra contains a series of chemical events due to the lack of oxygen. In this area, energy depletion occurs with destabilisation of the neuronal and surrounding cellular environment.
Neurotransmitters such as glutamate, calcium channel dysfunction, free radical release, and inflammatory changes occur with the end result of brain cell death. Brain tissue in the penumbra has full recovery potential and surrounds the already dead deeper brain tissue.
This penumbral area has been the subject of many studies. It is postulated to be the location to save during urgent treatment. This area can be visualised more clearly by special techniques in magnetic resonance imaging such as perfusion and diffusion weighted imaging. Simplistically, the former is the function of flow while the latter is a function of injured brain tissue.
Improvement in the management of acute stroke have been noted in the last decade. There are four proven treatments supported by the highest evidence. Firstly, the best evidence for stroke advancement has been the routine management of patients in Stroke Care Units (SCUs), which is effective in all stroke types.
These units are specially equipped, physical spaces for the acute care, monitoring, and treatment of stroke patients. Stroke care units also provide a focal point of activities or point of care for professionals and allied healthcare personnel. Stroke care within this centre is associated with better outcomes compared to patients cared for by visiting stroke teams or in general medical wards. Mortality is reduced by 20% while functional outcome after the stroke is improved by the same magnitude.
The exact components of stroke care management which is responsible for the effectiveness of SCUs are not clear but it is likely to be a combination of many factors such as early blood pressure monitoring and control, early mobilisation as well as compliance to important guidelines and best practices such as routine assessment and prevention of patients from venous thromboembolism after acute ischaemic stroke with low-molecular weight heparin or unfractionated low dose heparin.
The combination of these measures and effects of the highly specialised environment are likely to produce these extra benefits. (Venous thromboembolism are blood clots that form in the deep veins of patients who are at risk due to poor mobility, and most commonly, obesity.)
From a cost-benefit perspective, SCU management can prevent death or disability in 50 patients per every 1,000 strokes treated. This is in contrast to six patients benefiting per 1,000 patients treated with thrombolytics or clot dissolving medications and four patients per 1,000 for patients treated with aspirin or anti-platelet medications.
Hence, the widespread introduction of SCUs should be urgently established because of the benefits gained in the setting of limited resources, notably in developing countries where the rates of mortality from stroke is likely to be higher.
Thrombolysis or clot dissolution
Secondly, recombinant t-PA given through a patient’s veins is one of the most biologically active therapies for acute ischaemic stroke. Its function is to dissolve away blood clots that have formed in the blood vessel in a stroke. One person out of seven treated patients is likely to improve to the level of minimum or no neurological deficit.
However, as the numbers of patients treated are only relevant if started within three hours, the number of patients that can potentially benefit are much smaller. The overall cost-benefit when considering reducing disability as an outcome is only six patients per 1,000 ischaemic strokes. The drug does not reduce stroke mortality and only reduces stroke disability.
As the therapy is expensive and patients do not get to a stroke centre on time, many hospitals in developed countries do not offer thrombolysis. This is further compounded by the worldwide shortage of physicians who are expers in acute stroke management.
The public should also be aware that major side effects of thrombolytic treatment is symptomatic brain bleeding or haemorrhage. This has been observed in 6% to 7% of cases treated with thrombolytic therapy.
The major risk factors for brain haemorrhage in the above setting are greater age, high blood pressure, very severe neurological deficits, high blood glucose, and early ischaemic changes on the first CT scan of the brain.
The last factor is somewhat controversial because of the inclusion and analysis of clinical trial data which took account patients who were treated up to six hours. As such, it will be a heavily calculated decision for neurologists or physicians who treat acute stroke to give the therapy anyway.
Other modalities of treatment include the use of intra-arterial therapy within six hours of treatment, using another form of thrombolytic therapy such as prourokinase. Intraarterial treatment involves the use of injections of thrombolytic therapy directly into the main arteries of the brain. There is some evidence of results similar to intravenous trials but these treatments have not been approved by authorities worldwide and remain active in academic centres conducting various clinical studies.
Aspirin and other medications
Thirdly, the widespread use of aspirin within 48 hours of onset of ischaemic stroke is based on evidence from 40,000 patients which showed reduction in patient deaths and complications at 14 days after stroke. The cost-benefit factor demonstrated that nine patients will be saved from death and disability for every 1,000 patients treated.
Apart from its low cost, leading to its widespread use, the other advantages of aspirin are its easy administration and low adverse events when given acutely. The effectiveness of aspirin is likely to be related to early prevention of recurrence by thinning and reducing the clotting ability of blood but may also be useful in opening the vessel leading to the stroke penumbra.
As a fourth point, in 1% to 10% of stroke patients who have large ischaemic strokes, significant brain oedema develops two to five days after stroke onset. In such cases, 80% mortality is reported. Three major trials decompressed the brain of such patients within an average of 48 hours after diagnosis of the brain swelling, done by removing the skull bone(crainotomy). The combined data from these studies showed an impressive cost benefit advantage with one patient achieving good outcome after four patients were treated.
Reduction in stroke mortality is due to improved risk factor control. Modification of risk factors such as hypertension, cholesterol level, diabetes, and smoking have all been described.
Use of blood clotting prevention agents such as warfarin is useful in the context of atrial fibrillation. Use of aspirin in women older than 45 years is also useful as a primary prevention strategy ie before any strokes have occurred.
These stroke prevention strategies are urgently needed in developing countries where two-thirds of the mortality counts worldwide occur.
The prevention of recurrent stroke in patients who had a previous stroke is termed secondary prevention. Important milestones in the management of ischaemic stroke was achieved gradually. Thirty years ago, there was no proven secondary prevention treatment for ischaemic stroke.
Chronologically, medications such as aspirin was introduced in 1978, followed by aspirin plus dipyridamole in 1987, while procedures such as carotid endarterectomy for symptomatic carotid artery stenosis was developed in 1991, warfarin for atrial fibrillation in 1993, clopidogrel in 1996, blood pressure reduction with perindropril and indapamide or ramipril in 2001 and cholesterol reduction in 2006 were proven and validated via large clinical trials.
All ischaemic stroke patients should have a check-list of these interventions on discharge with regular review of these medications on follow-up and all stroke patients should work towards understanding how to reduce strokes after a previous one.
More specifically, anti-platelet medications prevent strokes by reducing the ability of blood to clot. This agents reduce strokes by 22% and mini or near strokes (transient ischaemic attacks) by 13%. Combining anti-platelet therapy to aspirin with an agent called extended release dipyridamole may double the effects of former.
Anti-platelet agents such as clopidogrel is slightly better than aspirin by the magnitude of 9% and may have some added benefits in the setting of coexisting heart disease and peripheral vascular disease.
Long term use of aspirin and clopidogrel to prevent recurrent strokes is offset by an increased risk of severe bleeding. A top limit to the beneficial effects of anti-platelet medications is likely to exist where side effects such as major bleeding takes away any advantage gained.
Warfarin is specifically active in atrial fibrillation or abnormal irregular rhythm of the heart. This agent, which acts on the coagulation pathway as opposed to platelets, reduces the risk of recurrent stroke by 70%. There is a small risk of major bleeding, notably brain haemorrhage (0.3%-0.6% per year).
Risk factors for major brain haemorrhage include age, high blood pressure, use of antiplatelet and warfarin in combination and increasing the amount of anticoagulation. In stroke patients without atrial fibrillation, warfarin is not a better agent compared to aspirin.
Other proven secondary prevention modalities
Patients with TIA or minor stroke with at least 70% partially blocked carotid artery of the neck will benefit from open carotid operations (carotid endarterectomy) to remove the partial blockage. This reduces the stroke risk by 60% over three years. This operation should be balanced against a operation complication rate of stroke and death of 5%. In patients without symptoms, the benefit is much smaller.
Other strategies include blood pressure reduction after stroke using specific agents such as perindropril and indapamide for a magnitude of reduction in recurrent stroke of 30% over five years irrespective of baseline blood pressure.
Cholesterol is a weaker risk factor for ischaemic stroke compared to patients with coronary artery disease. One study showed that intensive cholesterol reduction is beneficial for patients with ischaemic strokes and transient ischaemic attacks and prevented both fatal and non fatal stroke.
Surgical clipping of intracerebral aneurysms is proven to avoid recurrent haemorrhage after subarachnoid haemorrhage but the endovascular approach with coiling was shown to be better in terms of outcome with reduced operative complications. However, this is at the expense of a small increase in rebleeding later in life.
There is an increasing array of treatment strategies for stroke patients. The importance of stroke care units in reducing mortality is emphasised with the proposal to build a network of international SCUs for exchange of knowledge and experience.
A shortage of healthcare professionals to improve the care of stroke patients is evident and should be addressed urgently specifically in developing countries.
1. Donnan GA, Fisher M, Macleod M, Davis S. Stroke. Lancet. 2008;371:1612-23
2. Hacke W, Kaste M, Bluhmki E et al Thrombolysis with alteplase3 to 4.5 hours after acute ischaemic stroke. NEJM 359;1317-1329
Assoc. Prof. Dr Tan Kay Sin is a consultant neurologist and a full time academic staff at the Faculty of Medicine, University of Malaya where he teaches internal medicine and neurology. This article is contributed by The Star Health & Ageing Panel, which comprises a group of panellists who are not just opinion leaders in their respective fields of medical expertise, but have wide experience in medical health education for the public. The members of the panel include: Datuk Prof Dr Tan Hui Meng, consultant urologist; Dr Yap Piang Kian, consultant endocrinologist; Datuk Dr Azhari Rosman, consultant cardiologist; A/Prof Dr Philip Poi, consultant geriatrician; Dr Hew Fen Lee, consultant endocrinologist; Prof Dr Low Wah Yun, psychologist; Datuk Dr Nor Ashikin Mokhtar, consultant obstetrician and gynaecologist; Dr Lee Moon Keen, consultant neurologist; Dr Ting Hoon Chin, consultant dermatologist; Prof Khoo Ee Ming, primary care physician; Dr Ng Soo Chin, consultant haematologist. For more information, e-mail email@example.com. The Star Health & Ageing Advisory Panel provides this information for educational and communication purposes only and it should not be construed as personal medical advice. Information published in this article is not intended to replace, supplant or augment a consultation with a health professional regarding the reader’s own medical care. The Star Health & Ageing Advisory Panel disclaims any and all liability for injury or other damages that could result from use of the information obtained from this article.