6.6: Acute Stroke
By Dr Eduardo Sabaté and Dr Sunil Wimalaratna
With appreciation to the WHO/CVD Unit and Drs Julien.Bogousslavsky, Patrik Michel, and
Cesare Fieschi for their comments.
7 October 2004
6.6-1

6.6: Acute Stroke
Table of Contents
Abbreviations .......................................................................................................................................... 3
Summary .................................................................................................................................................. 4
6.6.1
Introduction ................................................................................................................................ 5
6.6.2
Burden of stroke ......................................................................................................................... 8
6.6.3
Control strategy ........................................................................................................................ 12
6.6.4
Major problem and challenges of stroke management: why does the disease burden persist? ....................................................................................................................................... 14
6.6.5
Past and current research into pharmaceutical interventions for managing stroke ...... 15
6.6.6
What are the opportunities for research into new pharmaceutical interventions that might fill the current gap and make a substantial difference? .......................................... 18
6.6.7
Conclusions ............................................................................................................................... 20
6.6.8
References ................................................................................................................................. 21
6.6-2

6.6: Acute Stroke
Abbreviations
COPD: Chronic Obstructive Pulmonary
Diseases
CT: computerized tomography
CVA: cerebrovascular accident
DALY: disability-adjusted life years
DWI: Diffusion-weighted imaging
EU: European Union
EU10: European Union’s new accession countries.
EU15: European Union with 15 countries
EU25: European Union with 25 countries
FDA: Food and Drug Administration
HL, hearing loss, adult onset
IHD: Ischaemic Heart Disease
LBW: low birth weight
LRI: Low Respiratory Infections
MRI: magnetic resonance imaging
NIHSS: National Institutes of Health Stroke
Scale
NINDS: National Institute of Neurologic
Diseases Study
ODD, other digestive diseases
OID, other infectious diseases
OUI: other unintentional injuries
QALY: Quality-adjusted Life Years rt-PA: recombinant tissue plasminogen activator
TBLC, trachea, bronchus, lung cancers
TIA: transient ischaemic attacks
6.6-3

6.6: Acute Stroke
Summary
Stroke is an abrupt onset of a focal neurological deficit secondary to a vascular event lasting more than 24 hours. An acute stroke refers to the first 24-hour-period of a stroke event. Stroke is classified as either ischaemic (caused by thrombosis or embolisms) or haemorrhagic (caused mainly by rupture of blood vessel or aneurysm).
The occlusion of the cerebral artery causes decreased blood flow and ischaemia. Depending on the severity of the ischemia, infarction (cellular death) will occur within minutes, causing irreversible damage even after blood flow is restored. This is called the “core” of the infarct.
Surrounding the core is tissue that is affected but functionally that may recover if blood flow is restored. This is called the “ischaemic penumbra”. Most people will have such an ischaemic penumbra amenable to treatment within the first 3 hours of occlusion of the cerebral artery, but many patients may have it up to 12 hours. This is the so-called “therapeutic window”.
Thus proper identification of treatable patients is crucial for the efficacy of the interventions.
Stroke is the second leading cause of death worldwide and in the European region. Ten per cent of the 55 million deaths that occur every year worldwide are due to stroke. The overall mortality from stroke has been declining both worldwide and in Europe. This is mainly due to improved access to appropriate health care, with the consequent rise in health care costs. In
Europe, discharges following hospitalization for stroke doubled during the last 15 years of the twentieth century. The United Kingdom spends 6% of its national health budget on stroke care, twice as much spent on ischaemic heart disease (IHD).
The successful management of acute stroke is based on imaging followed by two main strategies: vascular recanalization and supportive care. Differential diagnosis with haemorrhagic stroke is important. Restoration or improvement of perfusion to the ischaemic area is a key therapeutic strategy. However, currently available options, aspirin (1% better than placebo) and recombinant tissue plasminogen activator (rt-PA) (10% better than placebo) are not very effective. Current stroke therapy, therefore, is mainly based on general care and rehabilitation.
In most patients who have had a haemorrhagic stroke, current treatment focuses on evacuation of the haematoma particularly in the cerebellum, and supratentorial larger than
3 cm, despite the fact that trials have failed to show any benefit of this practice. If the haemorrhage is due to rupture of an aneurysm or AVM early surgical or endovascular intervention are important to avoid re-bleeding .
Despite improvements in care, sequelae of stroke remain a major problem. Fifty to seventy per cent of those who survive an ischaemic stroke will recover functional independence 3 months after onset, but 20% will require institutional care. Stroke is the third leading cause of disability and death in Europe after depression and IHD. Worldwide, stroke is the fifth leading cause of disability and death.
6.6-4

6.6: Acute Stroke
The economic impact of stroke care goes beyond the costs of sophisticated acute care, costly secondary prevention (carotid endarterectomy) and its prolonged high dependent institutional chronic care as well as costs of rehabilitation. Neither mortality rate nor hospital discharges accurately reflect the level of disability, which is mainly borne by patients and their families.
There is little progress being made in research and development of drugs for treating acute stroke, particularly in the field of neuroprotection. Surprisingly low levels of resources have been devoted to research and development of drugs for treating stroke during the last 30 years
(no more than 10% that invested in IHD or cancer).
Major improvements are needed in the chain of care for identification of stroke by relatives
(education); early treatment (possibly with aspirin); the prompt referral to an accident and emergency facility (mobile units); accurate diagnosis and fast appropriate treatment (protocols and specialized units); improving access to expanded and more efficacious therapeutic options; and prompt referral to rehabilitation services.
As “time is brain”, more efficacious treatments provided early in the chain of care are needed to minimise disability and avoid future suffering as well as reducing the economic costs in societies with higher ageing populations.
6.6.1 Introduction
Stroke, is defined as abrupt onset of a focal neurological deficit lasting more than 24 hours. It is also called cerebrovascular accident (CVA) or apoplexy.
1 An acute stroke refers to the first
24-hour- period of a stroke. Focal neurological deficit lasting less than 24 hours (usually 5–20 minutes) known as transient ischaemic attack (TIA) is relevant but beyond the scope of this discussion paper.
Stroke is classified on the basis of its aetiology as either ischaemic (80%) or haemorrhagic
(20%). Ischaemic stroke is produced by occlusion of a cerebral artery [thrombotic or atherosclerotic (50%), embolic (25%) and microartery occlusion, “lacunar stroke”, (25%)].
Haemorrhagic stroke is caused mainly by spontaneous rupture of blood vessels or aneurysms or secondary to trauma.
2 The International Classification of Diseases versions 9 and 10 has codified the different types as 430-438 and 160-169, respectively.
6.6-5

6.6: Acute Stroke
Neurological symptoms and signs of an ischaemic stroke usually appear suddenly, but less frequently, they occur in a progressive manner (stroke-in-progress). The typical presentation is the sudden onset of hemiparesis in an older person. Symptoms and signs vary depending on the location of the occlusion and the extent of the collateral flow.Atherosclerotic ischaemic
stroke is commoner in the elderly, and occurs without warning in more than 80% of cases. A
TIA a few months before the stroke is considered an important warning sign.
1 The pathophysiology is similar to that of ischaemic heart disease; an atherosclerotic plaque in a cerebral artery ulcerates triggering the aggregation of platelets and coagulation of fibrin to produce the thrombus that occludes the artery. Fewer than 20% of cases do not evolve to ulceration, but progresses to cause gradual obstruction of flow and may manifest as TIAs. In hypertension-induced arteriosclerosis, small penetrating arteries of the deep white matter of the brain are affected producing small infarctions known as “lacunar infarcts”. In around 40% of elderly stroke patients no clear origin of the infarction can be found.
.3;4
Embolic ischaemic stroke is more frequent in patients with atrial fibrillation (80%), myocardial infarction, prosthetic valves, rheumatic heart disease and larger artery atheroma
(artery-artery embolus). Most emboli are of atherosclerotic origin, and may partially or temporally obstruct cerebral arteries causing TIAs.
5 Embolisms tend to be multifocal and may produce small haemorrhages around the obstruction.
The occlusion of a cerebral artery causes a decreased blood flow and ischaemia. If it lasts only few seconds or a minute, recovery is immediate and complete. Depending on the severity of the ischemia, infarction (cellular death) will occur within minutes, causing irreversible damage even after blood flow is restored. This is called the “core” of the infarct. Surrounding the core is tissue that is affected functionally due to diminished circulation but may recover if blood flow is restored.
6-18 This is called the “ischaemic penumbra” of a stroke. Most people will have an ischaemic penumbra amenable to treatment for 3 hours, but many patients may have it up to 12 hours. This is known as the ‘therapeutic window’ available for thrombolysis.
Thus proper identification of treatable patients is crucial for the efficacy of the interventions.
Due to changes in the vessels and parenchyma caused by ischaemia, the flow may not be restored even after the original cause of the obstruction has been removed (“no-reflow phenomenon”). Oedema is present in all necrotic tissue. In large areas of necrosis, massive oedema compresses adjacent tissue, increasing intracranial pressure and may cause herniation of the brain, leading to death within a few days in 80% of cases.
19-23 Surgical decompression has been suggested for these cases. The extent of functional disability will depend on the extent and the localization of ischaemia and complications experienced by the patient.
5
6.6-6

6.6: Acute Stroke
Seizures at the time of stroke occur in 3–5% of infarctions, more often after embolism than thrombosis. The same proportion of patients will develop epilepsy from 6 to 18 months after a stroke. Idiopathic epilepsy in the elderly, therefore, may be the result of silent cortical infarction.
1
There are two types; one resulting from intracerebral haemorrhage secondary to hypertension or cerebral amyloid angiopathy, degenerative arterial disease and the other secondary to subarachnoid haemorrhages caused by rupture of an aneurysm. In the United States, 8–10 million people (3% prevalence) might have one aneurysm and bleeding occurs in only 30 000 people per year. Other causes are uncommon, and sometimes, no source for the haemorrhage can be found. The main risk factors are advanced age, heavy alcohol consumption and hypertension. Cocaine abuse is an important cause of cerebral haemorrhage in young people.
1
Most intracerebral haemorrhagic strokes develop over 30–90 min. Symptoms will depend on the location and extent of the haemorrhage. Focal neurological symptoms, vomiting and drowsiness are common. Headache may be present, but stiff neck and seizures are uncommon. Large haemorrhages may cause stupor or coma. Most sub-arachnoid haemorrhages appear suddenly with intense headache, vomiting and neurological deficit and altered consciousness may occur in about 50% of patients. Occasionally, prodromal neurological symptoms, such as paralysis of a limb, difficulty in speaking, visual impairment or sudden unexplained headache, appear before a haemorrhage from an enlarging aneurysm causing pressure on the surrounding tissue or as a result of a leak of blood into the subarachnoid space (“warning leaks”).
Cerebral vasospasm is an early complication and re-bleeding or hydrocephalus may be complications of SAH in 30% of cases during the first month, resulting in an extra 60% mortality. Of those who survive, more than half will have significant disabilities. The annual risk of recurrence of bleeding of an aneurysm is 3%. Thus, early surgical or intravascular treatment of aneurysm in these patients improves their long term outcome.
1 The effectiveness of evacuation of a supratentorial haematoma due to other causes has not been evaluated.
24
However, surgical removal of a large cerebellar haematoma is the current practice.
Outcome of investigations are crucial for effective management of acute stroke. Computerised tomography (CT) is widely available, fast and probably the most useful imaging method in identifying/differentiating cerebral haemorrhage from infarction. However, CT does not show any abnormality within the first hour of an ischaemic stroke. Magnetic resonance imaging
(MRI), on the other hand, may be more useful in identify an ischaemic stroke but it is more time consuming, not widely available in developing countries and special methods such as diffusion weighted imaging is available only in specialist centres in developed countries. MR or CT angiography demonstrates the cerebral vasculature and may add further information such as aneurisms, segmental narrowing or complete blockage of blood vessels. Doppler
6.6-7

6.6: Acute Stroke ultrasonography of carotid and vertebral vessels in the neck add further information – and is particularly useful in recommending patients for endarterectomy endovascular procedures or intravascular thrombolysis treatment. Angiography performed by injecting a radio-opaque dye directly into cerebral arteries via a catheter carries a significant risk of complications according to age, the experience of the operator, etc (0.13-3% risk of complications).
None of these procedures is capable of accurately identifying ‘ischaemic penumbra’ the most important area of brain that is amenable to treatment in a patient with acute stroke. Newer
MRI diagnostic techniques such as diffusion-perfusion-weighted (DPW) imaging have been tested for this purpose.
8-10;25-48 Diffusion-perfusion-weighted MRI and perfusion CT allows a rought estimation of the penumbra and core areas in the acute phase of stroke. Although it has been demonstrated that both MRI and CT can reliably detect intracranial haemorrhage in the acute phase, MRI is not widely available, and access to emergent CT may be a problem in some areas of Europe and the world. Further research into identification of neuronal integrity of the penumbra during the so-called ‘therapeutic window’ is essential for improving therapy for stroke.
The evaluation and treatment of patients with acute ischaemic stroke should be performed without delay. The general and neurological history, together with brain imaging provide the necessary information about the aetiology and potential contraindications to treatment with thrombolytic agents. Brain imaging is currently mandatory to guide acute interventions. The intervention protocols for haemorrhagic stroke are different from ischaemic stroke, and fatal complications may result from misdiagnosis. Other clinical and para-clinical tests required are not discussed here.
The National Institutes of Health Stroke Scale (NIHSS) has come into widespread use in the
United States for assessment of the severity of stroke and as an indicator of its prognosis. The initial NIHSS score provides important prognostic information.
Approximately 60–70% of patients with an acute ischaemic stroke with a baseline NIHSS score <10 will have a favourable outcome after 1 year as compared with only 4–16% of those with a score >20.
5
6.6.2 Burden of stroke
Stroke is the second leading cause of death at the global level and in the European region.
49 Ten per cent of the 55 million deaths that occur every year worldwide are due to stroke. Two-thirds of them occur among people living in developing countries.
50 Almost a
Graph 6.6.1: EU Stroke deaths
(2002, by age and sex)
Source: WHO, Evidence, Information and Policy, 2003
200'000
180'000
160'000
140'000
120'000
100'000
80'000
60'000
40'000
20'000
0
0-4 5-14 15-29 30-44 45-59
Age groups
60-69 70-79 80+
EU25-M
EU25-F
EU15-M
EU15-F
EU10-M
EU10-F
6.6-8

6.6: Acute Stroke million cases and two hundred thousand deaths due to stroke occur in the EU alone every year.
49;51 Together with cardiovascular diseases (CVD), these cases account for more than a third of all deaths in the EU (Table 6.6.2).
There is a substantial difference in mortality between males and females: it is higher in males under the age of 60 (1:1.7) and in females after the age of 70 (see graph 6.6.1). Overall stroke mortality has been declining worldwide despite the increased percentage of people aged over
65 years (75% of stroke victims are above 65 years old).
52 This is mainly due to decreased exposure to risk factors, mainly hypertension and smoking, and to improved access to better healthcare.
53 In Europe, stroke mortality is also declining although there are regional differences (Fig. 6.6.3).
Table 6.6.2: Leading cause of deaths worldwide and in Europe (2002, percentage of total deaths)
Global EU25 EU15 EU10
IHD (12.57%) IHD (18.11%) IHD (16.79%) IHD (24.45%)
Stroke (9.63%)
LRI (6.60%)
HIV/AIDS (4.95%)
Stroke (10.90%)
Other CVD (10.78%)
Other CVD (10.78%)
Stroke (10.42%)
Stroke (13.19%)
Other CVD (10.77%)
Trachea, bronchus, lung Trachea, bronchus, lung Trachea, bronchus, lung cancers (5.38%) cancers (5.31%) cancers (5.73%)
COPD (4.81%) LRI (4.01%) LRI (4.46%) Other cancer (3.96%)
IHD: Ischemic Heart Diseases; LRI: Low Respiratory Infections; CVD: Cardiovascular Diseases; COPD: Chronic Obstructive Pulmonary
Diseases; EU25: European Union with 25 countries; EU15: European Union with 15 countries; EU10: European Union’s new accession countries. Source: WHO, Evidence, Information and Policy, 2003.
Despite improvement in care, sequelae of stroke remains one of the major problems. Eight to twelve per cent of ischaemic strokes and 37–38% of haemorrhagic strokes result in death within 30 days.
54;55 Fifty to seventy per cent of patients who survive an ischaemic stroke will recover functional independence 3 months after onset, but 20% will require institutional care.
Among patients above the age of 65 years, the severity of the attack and permanent disability are greater. It has been reported that six months after the attack, 50% of stroke patients had some hemiparesis, 30% were unable to walk without assistance, 26% were dependent on others for help with activities of daily living, 19% had aphasia, 35% had depressive symptoms and 26% were being cared for in a nursing home.
56 Stroke in childhood showed a moderate or severe deficit in 42% of cases.
57 The burden of stroke can be reflected in a measurement such as disability-adjusted life years (DALYs) or Quality-adjusted Life Years (QALY). Table 6.6.4 the
6.6-9

6.6: Acute Stroke disability component of diseases in terms of DALYs, ranking stroke third in Europe after depression and IHD.
Graph 6.6.3: Standardized death rates cerebrovascular diseases, all ages per 100.000
Source: Health for All Database, WHO-EURO 2004
090302 +SDR, cerebrovascular diseases, all ages per 100000
150
140
130
120
110
100
90
80
70
60
50
1970 1980 1990 2000 2010
EU-25 average
EU-15 (MSs prior 1.5.2004) average
EU-10 (MSs after 1.5.2004) average
Table 6.6.4 : Burden of diseases and injury worldwide and in Europe (2002, percentage of total DALYs)
LRI (5.83%)
Global EU25
Depression (7.76%)
EU15
Depression (7.87%)
EU10
IHD (9.98%)
HIV/AIDS (5.77%)
Depression (4.51%)
Diarrhoea (4.10%)
IHD (3.91%)
Stroke (3.29%)
OUI (3.26%)
LBW (3.11%)
IHD (7.40%)
Stroke** (5.27%)
Alcohol use (4.21%)
Other CVD (3.85%)
Alzheimer* (3.48%)
HL (3.43%)
TBLC (3.28%)
IHD (6.76%)
Stroke** (5.03%)
Alcohol use (4.36%)
Alzheimer* (3.91%)
Other CVD (3.83%)
HL (3.61%)
COPD (3.44%)
Depression (7.31%)
Stroke** (6.23%)
Other CVD (3.94%)
Alcohol use (3.57%)
TBLC (3.43%)
OUI (3.40%)
ODD (3.37%)
Malaria (3.00%)
OID (2.68%)
COPD (3.05%)
ODD (2.79%)
TBLC (3.25%)
ODD (2.64%)
Osteoarthritis (2.76%)
HL (2.69%)
* Alzheimer and other dementias; ** cerebrovascular diseases; LRI, lower respiratory infections; IHD, ischaemic heart disease; OUI, other unintentional injuries; LBW, low birth weight; OID, other infectious diseases; HL, hearing loss, adult onset; TBLC, trachea, bronchus, lung cancers;
COPD, chronic obstructive pulmonary disease; ODD, other digestive diseases. EU25: European Union with 25 countries; EU15: European
Union with 15 countries; EU10: European Union’s new accession countries. Source: WHO, Evidence, Information and Policy, 2003
6.6-10

Due to ageing populations, especially in those countries currently undergoing rapid economic growth, projections to
2020 suggest that stroke will remain the second leading cause of death. In addition, stroke will be among the five most important causes of disability in both developing and developed countries 50 (Table 6.6.5).
There are no projections available for the EU).
6.6: Acute Stroke
Table 6.6.5: Burden of disease and injury (DALY, global)
1. Acute lower respiratory infections
2000
2. Human immunodeficiency virus/acquired immunodeficiency syndrome
3. Perinatal conditions
4. Diarrhoeal diseases
2020
1. Ischaemic heart disease
2. Unipolar major depression
3. Road traffic accidents
4. Cerebrovascular disease
5. Chronic obstructive pulmonary disease
5. Unipolar major depression
6. Lower respiratory infections
The largest components of acute
6. Ischaemic heart disease
7. Tuberculosis care costs in the United States are room charges (50%), medical
7. Cerebrovascular disease
8. War
Fig. 6.6.6: Hospital discharges, Cerebrovascular disease,
(19%).
58 The economic impact of stroke goes beyond the cost of acute care to include per 100.000; Source: WHO Health for All Database. cerebrovascular diseases per 100000
10. Human immunodeficiency sophisticated and costly secondary prevention such as carotid endarterectomy virus
350 chronic care. The estimated mean lifetime cost per ischaemic stroke patient in the
United States is US$ 140,048 in 1999. This includes inpatient care, rehabilitation and follow-up care necessary for lasting disabilities.
59 In 2004 the estimated total direct and indirect cost of stroke in the
United States is US$ 53.6 billion.
52
300
250
EU-25 average
EU-15 (MSs prior 1.5.2004) average
EU-10 (MSs after 1.5.2004) average
200
1980 1985 1990 1995 2000 2005 2010
In the European Union, hospital discharges for cerebrovascular diseases almost doubled during the last 15 years of the twentieth century (Fig. 6.6.6) In the United States, the same pattern has been reported for the same period.Average length of hospital stay fell from 11.1 to
6.2 days and the total number of person–days in hospital decreased by 22%.60 Specialized stroke care has been shown to improve health and economic outcomes.
61;62 Similar trends are observed for mortality and case fatality rate could be lowered by improved stroke services.
Neither mortality rate nor discharges from hospital accurately reflect the level of disability, which is mainly borne by patients and their families. Stroke has been associated with greater use of informal care (family and friends).
63 Health care costs are increasing despite the decrease in stroke incidence and mortality, and will continue to increase as our societies age.
6.6-11

6.6: Acute Stroke
Priorities, therefore, should be placed on primary prevention of stroke, effective treatment of acute stroke to minimise unfavourable sequelae and extend stroke management outside the hospital to improve accessibility and reduce hospital costs.
6.6.3 Control strategy
Stroke prevention is still the best available intervention. High blood pressure is one of the major primary and secondary risk factors for stroke, for which major professional associations worldwide have published detailed clinical management guidelines that might be highly costeffective in high-risk populations.
64-66 Reducing other risk factors, such as smoking, diabetes
(obesity and lack of exercise), and heavy alcohol consumption have been shown to provide health benefits including reduction of stroke and might be highly cost-effective.
67
The successful management of acute stroke is based on two strategies: a) Vascular recanalization
Because most strokes are due to thromboembolic occlusion of an intracranial artery, restoration or improvement of perfusion to the ischaemic area is the key therapeutic strategy.
The concept of an “ischaemic penumbra”, a potentially recoverable brain tissue, allows early intervention to improve the neurological symptoms, and decrease the functional disability after the attack.
There are many strategies suggested for treatment of acute stroke, but only oral aspirin and intravenous rt-PA have been clearly proven to be effective and their use has now been approved by regulatory agencies.
24
Anti-platelet Agents: The use of antiplatelet agents is highly controversial. Aspirin, 150–300 mg once by mouth, has been found one percent more effective than placebo in reducing death and disabilities at 6 months after onset in patients with ischaemic stroke. There has been no increased risk of death among those subsequently found to have a haemorrhagic stroke.
68;69
Some authors recommend not delaying the administration of aspirin even if imaging diagnosis is not available during the first 48 hours 24 or haemorrhagic stroke has been excluded by CT or MRI.
2 Side-effects such as abdominal pain, peptic ulcerations and allergy to Aspirin may limit its wider use.
70 Clopidogrel is an alterative when aspirin cannot be used.
Anticoagulants, such as Warfarin, have not been shown to produce better outcomes than aspirin alone .71
No other antiplatelet agent has yet been reported effective.
24;72
Thrombolysis: The intravenous administration of rt-PA (0.9 mg/kg; maximum dose 90 mg) within 3 hours of onset of ischaemic stroke has been approved by the US Food and Drug
Administration (FDA) and EU regulators for the treatment of acute ischaemic stroke.
45
6.6-12

6.6: Acute Stroke
Treatment with rt-PA is associated with potentially fatal intracranial haemorrhage in 6.3% of cases (versus 0.6% of cases treated with placebo). The safety and efficacy of rt-PA for the treatment of children has not been established. Common side-effects include bleeding from cuts, gums, wounds, injection sites, fever and low blood pressure.
73 Because of potential fatal complications thrombolytic treatment should be carried out according to a strict predetermined protocol.
To date, no other thrombolytic agent has been established as a safe and effective alternative to intravenous rt-PA. Currently available data do not support the clinical use of either streptokinase or ancrod.
24;74 Promising results have been reported in trials of prourokinase, but the risk of haemorrhagic stroke is high.
75-77
As the ischaemic process progresses very fast, the time at which treatment starts has been shown to be critical if there are to be significant benefits. Treatment within the first 3 hours has been defined as the ‘therapeutic window’ for acute stroke, but evidence suggests that earlier treatment brings a better outcome.
As Intracranial haemorrhage is difficult to treat it must be avoided at all costs. In the National
Institute of Neurologic Diseases Study (NINDS) of rt-PA showed the NIHSS score to be useful in identifying patients with higher haemorrhagic risk. Patients with a score of 20 or more on the NIHSS had a 17% chance of intracranial haemorrhage, whereas the risk of bleeding was only 3% among those with a score <10.
5
The size of the infarct, based on CT, is also a predictor of haemorrhage and poor outcomes, but no study has yet determined whether treatment of severe cases with rt-PA might have higher risks than benefits. As a result, it has been suggested that the performance of these tests should not delay treatment with intravenous rt-PA.
5 Other investigations, including imaging of cerebral vessels, carotid Doppler studies, cardiac echo can be delayed until after the thrombolytic treatment. b) Supportive care
When cerebral infarction occurs, the immediate goal is to optimize cerebral perfusion of the ischaemic area, monitor potential stroke-related complications (cerebral oedema, seizures, haemorrhagic transformation, cardiovascular and pulmonary problems, fever and malignant hypertension) and to prevent the common complications of bedridden patients, such as malnutrition, infections, pressure sores, aspiration pneumonia, deep venous thrombosis and pulmonary embolism. Early mobilisation is very useful in preventing these complications.
The provision of airway support and ventilatory assistance for patients with acute stroke who have depressed levels of consciousness or airway obstruction may be necessary. A further recommendation is to provide supplementary oxygen only to hypoxic patients. Fever is associated with poor outcomes and should be treated with antipyretics with no antiplatelet effect. There is general agreement to recommend control of hypoglycaemia or hyperglycaemia following stroke. A reasonable goal would be to lower markedly elevated glucose levels to
<300 mg/dL (<16.63 mmol/L).
1
6.6-13

6.6: Acute Stroke
As cardiovascular diseases (mainly myocardial infarction and arrhythmias) are risk factors and complications of an acute stroke, they should be carefully evaluated and treated using established protocols in stroke patients. Use of anticoagulants during the first 14 days should be avoided. Hypertension may be a serious complication is some cases, but there is no evidence to support aggressive treatment unless systolic blood pressure is >220 mmHg or the diastolic blood pressure is >120 mmHg.
78
Once the patient has been stabilized patient and family education, screening and treatment of depression, and physical and functional rehabilitation should start as soon as possible. Finally, the patient should have further evaluation to determine the cause of the stroke, and medical or surgical therapies should be administered to prevent recurrent ischaemic events.
Acute haemorrhagic stroke
In most patients with a haemorrhagic stroke, bleeding has already stopped by the time they arrive at the hospital. Except in patients with a bleeding disorder, nothing can be done about the haemorrhage itself. Nevertheless, Mayer et al recently reported that early administration of clotting factors may be beneficial for all patients.
79 The assessment should be done in consultation with a neurosurgeon. The size and location of the haematoma determine the prognosis. current treatment focuses on evacuation of the haematoma particularly in the cerebellum, and supratentorial larger than 3 cm, despite the fact that trials have failed to show any benefit of this practice.
24 If the cause is rupture of an aneurysm, pain management and early surgical or endovascular repair of the aneurysm are important to avoid re-rupture (60% risk with poor prognosis).
Antifibrinolytic agents may be used in patients in whom treatment is delayed. They are associated with a reduced incidence of aneurysmal re-rupture but are also associated with an increased incidence of delayed cerebral infarction. Because of the increased risk of ischaemic complications, antifibrinolytics are not routinely given to patients who are at risk for developing vasospasm.
6.6.4 Major problem and challenges of stroke management: why does the disease burden persist?
The process of care begins with calling an ambulance or personally on arriving in an accident and emergency facility. In one study in an urban area in the United States, only 17% of patients were admitted to hospital within the 3 hour therapeutic window 80 and in an international trial, only 4% of patients were admitted within 3 hours of symptoms onset.
69
Inadequate public education on stroke and the patient’s perception that his or her symptoms are not severe enough are the major causes of delays in attending a health service in developed countries. Only 5% of patients in developed countries have access to tr-PA within the “therapeutic window” and mobile stroke units are still at the experimental stage.
69 Lack of access to general health services might be an important factor in delayed treatment in developing countries.
6.6-14

6.6: Acute Stroke
Once the patient is in contact with the health system a number of major barriers to treatment within the therapeutic window have been identified. Lack of specific protocols and training , delay in obtaining a diagnostic imaging test, delay in referring the patient to a specialized stroke unit and the low efficacy of available treatments (aspirin 1% and rt-PA 10% superior than placebo) are some of these factors in developed and developing countries. Lack of access to rt-PA might be an important factor in developing countries.
Most patients with stroke are over the age of 65 years, and often present comorbidities that add complexity to the management of the condition. Stroke is highly unstable during the acute phase and requires close monitoring and prompt attention to complications. Access to highly skilled professionals and the availability of costly resources have been shown to improve overall outcomes.
72;81 The integration of rehabilitation services with acute hospital care has also been shown to be effective in improving health outcomes.
81
Thus the major challenge of stroke are facing the world population at large are early diagnosis and referral of patients to specialized units; the inadequate number of highly specialized professionals, unavailability of complex and costly care, limited therapeutic options, and the low efficacy of the available interventions.
An additional yet extremely important challenge is the insufficient funding for research and development of new products and protocols for stroke management. Funding for stroke research falls far behind the resources devoted to other major conditions, such as ischaemic heart diseases and cancer.
82;83
6.6.5 Past and current research into pharmaceutical interventions for managing stroke
Progress in stroke research has been modest but significant. Developments in vascular and functional brain imaging have improved the detection of patients at increased risk and in the future it might be possible to identify those who are likely to benefit from a specific intervention. Developments in cell biology and new imaging techniques have improved our understanding of cerebral ischaemia.
The National Institutes of Health reported on 101 ongoing clinical studies on stroke, of which
35% evaluate the natural history of stroke, including risk factors, normal and pathological physiology, and descriptive epidemiology; 14% on prevention; 1% on diagnosis; 26% on rehabilitation; 11% on acute stroke treatment (1% thrombolytic coadjutants, 4% thrombolytic agents, 1% antiplatelets, 3% neuroprotectors and 2% cellular modulators); and 13% on alternative treatments and treatments for stroke-related comorbidities.
84
The Stroke Trials Directory details ongoing and already completed clinical trials throughout the world 85 (Tables 6.6.7 and 6.6.8). From these, only three new products have shown promising results; Pro-urokinase 75 and Tenecteplase, intra-arterial thrombolysis agents, and
Ancrod, 86 a defibrinogenating agent. All other trials have either failed to show benefits or have
6.6-15

6.6: Acute Stroke higher risks than benefits, while some are still in the early stages, so no conclusions could yet be drawn.
All neuroprotective agents that have shown positive results in animal models have failed when tested in humans (Table6.6.8). Many possible explanations for this failure have been proposed. For example, animal models were not designed to represent the realities of human health care (eg. difficulties with early treatment), inadequate translational techniques, underpowered phase III trials, inclusion of patients unlikely to respond to the trial drugs, and inappropriate measurement end-points.
72
6.6-16

6.6: Acute Stroke
Table 6.6.7: Drugs to improve blood flow
1) Anti-thrombotic: a) Heparin (NB) b) Low-molecular-weight heparins: i) Dalteparin (PO/OT) ii) Enoxaparin (Un) iii) Nadroparin (NB/PH) iv) Tinzaparin (AT/OT) v) Danaparoid (NB)
2) Anti-platelet a) Aspirin (B) b) Abciximab (AT/OT) c) Tirofiban d) Clopidogrel
3) Fibrinogen-depleting a) Ancrod (NB/OT) b) Defibrase (Un)
4) Improve capillary flow a) Pentoxifylline (Un)
5) Thrombolytics a) Pro-urokinase (B/OT) b) Streptokinase (H) c) Tenecteplase (B/OT) d) Tissue plasminogen activator (B/FDA) e) Urokinase (Un) f) Desmoteplase
Symbols:
AT/OT: Acute treatment/ongoing trials
B/FDA: Beneficial/FDA approved for stroke
B/OT: Beneficial/ongoing trials
B: Beneficial
H: Harmful
NB/OT: No benefits/ongoing trials
NB/PH: No benefits/potential harm
NB: No benefits
OT: Ongoing trials
PO/OT: Prevention only/ongoing trials
S/OT: Safe/ongoing trials
Un: Unknown
6.6-17
Table 6.6.8: Drugs to protect brain tissue
1) Calcium-channel blockers a) Nimodipine (B/FDA for haemorrhagic stroke and NB/OT for ischaemic) b) Flunarizine (NB)
2) Calcium chelator a) DP-b99 (S/OT)
3) Free radical (antioxidants & nitrone traps) a) Ebselen (NB/OT) b) Tirilazad (NB/PH) c) NXY-059
4) GABA agonists a) Clomethiazole (NB)
5) Glutamate antagonists (NB or OT) a) AMPA antagonists: GYKI 52466; NBQX;
YM90K; YM872; ZK-200775 (MPQX) b) Kainate antagonist i) SYM 2081 c) NMDA antagonists i) Competitive NMDA antagonists
(1) CGS 19755 (Selfotel) ii) NMDA channel blockers: Aptiganel
(Cerestat); CP-101,606 ; Dextrorphan
; Dextromethorphan ; Magnesium ;
Memantine ; MK-801 ; NPS 1506 ;
Remacemide iii) Glycine site antagonists: ACEA 1021
; GV150526 iv) Polyamine site antagonists: Eliprodil
; Ifenprodil
6) Growth factors (NB/PH) a) Fibroblast growth factor (bFGF)
7) Leukocyte adhesion inhibitor a) Anti-ICAM antibody (H) b) Hu23F2G (NB)
8) Nitric oxide inhibitor a) Lubeluzole (NB)
9) Opioid antagonists a) Naloxone b) Nalmefene (NB/PH/OT)
10) Phosphatidylcholine precursor a) Citicoline (CDP-choline: NB)
11) Serotonin agonist a) Bay x 3072 (OT)
12) Sodium channel blockers a) Fosphenytoin (NB) b) Lubeluzole (NB) c) 619C89 (OT)
13) Potassium channel opener a) BMS-204352 (NB)
14) Mechanism unknown or uncertain a) Piracetam (NB) b) Lubeluzole ((NB)

6.6: Acute Stroke
Investment in research and development on stroke is minute compared to the funding available for the other two major conditions, CHD and cancer, and this is totally out of proportion to the burden caused by the illness. Rothwell found that funding for stroke research in the United Kingdom, was only 5% of the available funds of the biggest donor in this area, the British Heart Foundation, and only 2% of the amount devoted to research on cancer by the two largest cancer foundations, the Imperial Cancer Research Fund and the
Cancer Research Campaign. In the USA, the American Heart Association, devotes only 4.6% of its funding to stroke. The same pattern is seen in disease-specific governmental organizations, such as that of the EU and the National Institute of Neurological Disorders and
Stroke (US$ 200M of an overall annual budget of US$ 900 Millions).
82 Pendlebury et al has shown that this pattern is fairly homogeneous among nine European countries studied.
83
The UK National Health Service (NHS) spends ₤ 2.3 billion on stroke care annually, which represents 6% of its overall budget. Stroke in comparison to CHD utilizes almost twice as much health care resources and places a much greater financial burden on disabled patients and their families.
82 Yet resources dedicated to stroke research and development are a mere one tenth of those devoted to CHD. This is just 0.2% of the overall budget for stroke care of the UK National health services.
There is an evident mismatch between the funds allocated to research and development and the burden of stroke, whether measured in terms of mortality or disability. Lack of funding undermines the capacity to do good research to an extent that stroke scientists are no longer able to apply for the further required funding. For many years, this has been a vicious cycle that has delayed progress in stroke research. Rational decision-making processes, taking into consideration the burden of diseases, are used by governments to decide the amount of public expenditure to be directed towards pharmaceutical and medical technologies in developed countries. The same tools or adaptations of these tools should be used for guiding investment decisions on pharmaceutical research and development.
6.6.6 What are the opportunities for research into new pharmaceutical interventions that might fill the current gap and make a substantial difference?
Opportunities for research can be divided into four categories: a) reducing treatment delays; b) identifying those patients who can benefit the most from a product; c) prolonging the treatment window; and d) therapies that work outside the treatment window.
6.6-18

6.6: Acute Stroke
The use of rt-PA in mobile stroke units at the first contact with the patient and prompt referral to specialized centres, has been highly effective in improving health outcomes. As rt-PA is contraindicated in patients with haemorrhagic stroke or those likely to have it as consequence of the treatment, research is required to develop and test diagnostic protocols to be used by the paramedics in these units. In order to avoid duplication of ambulance systems, the use of rt-PA by paramedics should be considered in normal ambulances rather than in mobile stroke units. The current major drawback is inaccessibility to CT scanning.
Another area of research is the development of safer drugs that could be used earlier in sequence with stronger intervention later in hospital. Aspirin is shown to be effective in improving health outcomes in acute stroke. It is safer for patients with haemorrhagic stroke and is readily available. Further research is required to evaluate the cost-effectiveness of using aspirin at the time of onset of symptoms at home, in the ambulance or on arrival at the hospital in relation to its interaction with rt-PA at different dosages; and the additional risk for patients with haemorrhagic stroke that may have been misdiagnosed as ischaemic stroke.
Drug efficacy may be lower and/or drugs may have a higher profile of side-effects for erroneous reasons, e.g. trials may have included patients who no longer have an ischaemic penumbra, or who have experienced different physiopathological mechanism, or who were admitted using different concomitant treatment. Such patients should be identified and included in trials designed specifically for them.
Diagnosis using perfusion–diffusion MRI and CT may delineate the existence and extent of the ischaemic core, the extent and severity of perfusion impairments, occlusion of large vessels, and the ischaemic penumbra. It has also shown promising results in predicting health outcomes and identifying patients with treatable ischeamic penumbra beyond the standard 3hour therapeutic window. Several studies are currently evaluating some of these issues (the
DWI Evaluation for Understanding Stroke Evolution (DEFUSE), the Echo Planar Imaging
Thrombolytic Evaluation Trial (EPHITHET), the Desmoplase in Acute Stroke (DIAS) and the
Stroke Evaluation for Late Endovascular Cerebral Thrombolysis). Further research is needed to evaluate feasibility of these techniques to be used clinically in resource-poor settings and also to be able to match specific treatments to specific patients using more advanced techniques.
Therapies with the so-called neuroprotectives that is aimed at slowing down the cascade of events leading to cell death have been tested, but the results have been disappointing. These unfavourable results might have been the product of many methodological errors. If neuroprotectors are to be effective in slowing down cell death this may be very useful in
6.6-19

6.6: Acute Stroke prolonging the therapeutic window, and therefore the management of acute stroke. Some publications have suggested that it would be beneficial to begin the use of neuroprotector earlier in the chain of care, before treatment with fibrinolytic agents.
72 More funding is urgently needed in this specific area of research.
Many therapies that are not indicated in the early stages of care because of serious complications such as cerebral haemorrhage, but they may be useful at later stages when haemorrhages are less likely to occur. Some other therapies target mechanisms that appear several hours after the onset of the symptoms. Exploitation of such therapies will significantly increase the number of patients that could be treated leading to major improvements in healthcare provision.
6.6.7 Conclusions
Ischaemic stroke produces irreversible cellular death within a few minutes. Surrounding the ischaemic core is the tissue that is affected by ischaemia, but still functional and recoverable.
Any therapeutic measures should be directed in stopping the progression of the ischaemia and achieving functional recovery of tissue as soon as possible. The nature of the disease is such that time is the major constraint in the management of acute ischaemic stroke. Hence the phrase “time is brain”, has been coined by workers in this field.
The management of patients with acute ischaemic stroke requires multiple interventions, an accurate initial diagnosis, close monitoring of potential complications and skilled highly trained professionals. The evidence suggests that mortality can be reduced further and neurological disability can be avoided or improved with the appropriate treatment of acute stroke.
Major improvements in stroke care have been made in recent years. Rapid referral of patients to a specialized stroke unit, the administration of rt-PA within the 3 hour therapeutic window and the provision of intensive general care, have made a real difference.
There is a still long way to go. Major improvements are needed in the chain of care, in the identification of an attack by relatives (education), early treatment (aspirin?), the prompt referral to an accident and emergency facility (mobile units), accurate diagnosis and fast and appropriate treatment (protocols and specialized units), improving access to efficacious therapeutic options, and prompt referral to rehabilitation services.
The results of trials of therapies currently in the pipeline have been disappointing, especially in the field of neuroprotectors. This is not different to the situation with many other conditions in the early stages of research. The difference is that due to insufficient funding stroke research had suffered and had not made major advancement in 30 years!
6.6-20

6.6: Acute Stroke
The decrease in mortality is due to the provision of complex and costly general care and not as a result of salvaging the ischaemic brain by specific stroke therapy. Most patients sadly have significant disability when they are discharged from the hospital where the society is expected to support.
More efficacious treatments provided earlier in the chain of care are needed to avoid future suffering and the economic cost of increasing disability in rapidly ageing societies.
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6.6-26