Review of Literature

Review of

Literature
Historical Review

Cerebrovascular accidents have been known since ancient times

because of the striking clinical picture they produce. As early as 400 BC

Hippocrates described stroke as apoplexy, which means astonishment. The

Greeks recognized that interruption of blood vessels to the brain could cause

loss of consciousness. They named the arteries ‘Karos’ meaning deep sleep

from which the carotid arteries derive their name.

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 Review of Literature

Galen (131-201AD) dissected the brain of animals and described the

anatomy of brain and blood vessels. Andreas Versailus (1514-1564) went a

step further and dissected human brain. His observations were published in ‘De

Humani corpis FabrInternal Carotid Artery’.

Thomas Willis (1621-1675) described the hexagonal network of arteries

at the base of the brain in his work ‘Cerebrainotome’. The arterial network is

still called by his name-The circle of Willis. The carotid siphon and the course

of the middle cerebral artery in the Sylvian fissure were mapped by Jacob

Wepfer (1630-1695).

In the eighteenth century, Giovanni Batiste Morgan (1628-1771)

established that lesions in the brain are seen on the contralateral side of

paralysis. Jean Martin Charcot (1825-1893) described aneurysms and

emphasized their importance in cerebrovascular accidents. William Sen House

Kirles (1852) was the first to give description of cerebral embolism. Panam first

proposed that debris from atherosclerotic plaques can cause emboli.

In 1838, Dechambre coined the term ‘Lacune’, Pierre Marrie described

50 cases of capsular infarction of the lacunar type. The ischemic etiology of

lacunar infarcts was firmly established by Cecil and Oscar Voght of Germany.

The contributions of Foix and his colleagues in the 20th century gave

clinicopathologists an understanding of the syndromes of infarction in the

middle cerebral artery, anterior cerebral artery and vertebrobasillar artery

territories.

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 Review of Literature

Loman and Myerson in 1936 introduced coronary angiography.

Godfrey Hounsefield in 1972 invented CT scan and has revolutionized the

diagnosis and treatment of stroke.

By the early 1980s with the introduction of B mode continuous wave and

pulsed Doppler ultrasound technology, the extracranial carotid arteries received

attention. The focus was now on an occlusive extracranial arterial disease and

their contributions to stroke.

Medical as well as surgical treatment of stroke changed dramatically with

the above clinicopathological and technological advances. In 1950, Craven

discovered the antithrombotic properties of aspirin. During the last two decades

other antiplatelet drugs and thrombolysis have become popular. Surgical

modalities of treatment are also gaining popularity. The first

thromboendarterectomy was performed by DeBakey in August 1953 and is

being increasingly resorted to, today as a preventive measure.

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DEFINITIONS AND CLASSIFICATIONS

Stroke

A clinical syndrome characterised by rapidly developing clinical

symptoms and/or signs, and at times global, loss of cerebral function, with

symptoms lasting more than 24 hours or leading to death, with no apparent

cause other than a vascular one.1,25

Transient Ischaemic Attack (TIA)

Transient Ischaemic Attack was defined as an acute loss of ocular or focal

cerebral function lasting less than 24 hours that was presumed to be due to

ischemic vascular disease.26

Transient Ischaemic Attack in the emergency department have a high risk

for stroke within the next 48 hours, it is imperative for the clinician to recognize

this golden opportunity to prevent a disabling stroke.27

Stroke is a clinical syndrome divided into two broad categories that define

its pathophysiology:

• Ischaemic strokes are caused by sudden occlusion of arteries supplying the

brain, either due to a thrombus at the site of occlusion or formed in another part

of the circulation. It account for 50%–85% of all strokes worldwide.28

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 Review of Literature

• Haemorrhagic strokes are caused by subarachnoid haemorrhage – bleeding

from one of the brain’s arteries into the brain tissue or intra-cerebral

haemorrhage - arterial bleeding in the space between meninges. This category

of stroke account for 1%-7% and 7%-27% respectively of all strokes

worldwide.28

Ischemic Stroke classification

There are many stroke sub-classification systems available; however the

Oxfordshire Community stroke project sub classification is suitable for use at

the bedside. Previous studies have shown that the Oxfordshire Community

stroke project (OCSP) clinical syndrome diagnosed in the hyperacute phase of

stroke correlates with clinical outcome.29

The Oxfordshire Community stroke project sub classification 30

Total anterior circulation infarct (TACI): This implies a large cortical

stroke in the middle cerebral, or middle and anterior cerebral artery territories.

Patients present with a combination of the following symptoms-

• New higher cerebral dysfunction e.g. Dysphasia, dyscalculia,

visuospatial disorder and

• Homonymous visual field defect and

• An ipsilateral motor and/or sensory deficit involving at least two out of

three areas of face arm or leg.

Partial anterior circulation infarct (PACI): This implies cortical stroke in

middle or anterior cerebral artery territory.

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 Review of Literature

Patients present with two out of three symptoms of the TACI OR new

higher cerebral dysfunction alone OR a motor/sensory deficit more restricted

than those classified as LACI (e.g. isolated hand involvement).

Lacunar Infarct (LACI): This implies a subcortical stroke due to small

vessel disease

• Pure motor stroke

• Pure sensory stroke

• Sensorimotor stroke

• Ataxic hemiparesis

Evidence of higher cortical involvement or disturbance of consciousness

excludes a lacunar stroke.

Posterior Circulation Infarct (POCI):

• Ipsilateral cranial nerve palsy with contralateral motor and/or sensory

deficit.

• Bilateral motor and/or sensory deficit.

• Disorder of conjugate eye movement.

• Cerebellar dysfunction without ipsilateral long tract involvement.

• Isolated homonymous visual field defect.

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EPIDEMIOLOGY

Reliable morbidity and mortality estimates for stroke in India are limited

due to incomplete death certification, incorrect death classification, and

uncertainty of etiology in cases of sudden death or multiple co-morbidities. 31

World-wide over the past four decades, the annual age-standardized stroke

incidence rate has decreased by 1.1% in high-income countries but has

increased by 5.3% in low to middle income counties. 28 The incidence and

prevalence of stroke in various regions of the world is shown in Table 1.

Table 1: Regional Incidence and Prevalence of Stroke

Region Incidence (Million) Prevalence (Million)

World 9.0 30.7

Africa 0.7 1.6

Americas 0.9 4.8

Eastern Mediterranean 0.4 1.1

South East Asia 1.8 4.5

Western Pacific 3.3 9.1

12.6 million have moderate-severe disability.

8.9 million out of 12.6 million is in low and middle income countries.

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Source: International agenda for stroke (Fisher 2011). 32 Global

conference on healthy lifestyle and non-communicable disease control Moscow.

Morbidity and Mortality associated with Stroke

Global Stroke Morbidity and Mortality

 400-800 strokes per 100,00033

 5.7 million deaths 34

 16 million new acute strokes every year 3

 28,500,000 DALYs (disability adjusted life-year)35

 28-30 day case fatality ranges from 17%-35% 28

Stroke Morbidity and Mortality in India

 Prevalence 90-222 per 100,000 36

 102, 620 million deaths 37

 1.44-1.64 million cases of new acute strokes every year 38, 39

 6,398,000 DALYs (WHO 2009)40

 12% of strokes occur in the population aged <40 years 41

 28-30 day case fatality ranges from 18-41%15,42

Sex differences in stroke epidemiology

The incidence of stroke is higher in men until advanced age, with a

higher incidence of stroke in women after age 85 years. 43 Each year more

women than men die from stroke, with women accounting for 61% of deaths in

the US in 2004.43 This difference may result from a combination of the longer

life expectancy of women and the increasing incidence of stroke with age.

There is a trend for increased stroke severity 44 and greater mortality in women

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 Review of Literature

versus men after stroke.43 Of those with a first stroke, the percentage of those

with a recurrent stroke within 5 years is higher in women than in men (22% of

women vs. 13% of men 40–69 years old; 28% of women vs. 23% of men 6 70

years old).43

Risk Factors of Stroke

Once stroke has occurred, the management strategies are limited and the

disability it leaves behind is often devastating. With advances in our knowledge

of risk factors and precipitating events the emphasis has now shifted to stroke

prevention. Like in coronary artery disease, primary prevention can go a long

way in preventing stroke.

Risk factors may be classified as modifiable or nonmodifiable.

Non-modifiable

 Age

 Gender

 Race/Ethnicity

 Family history

 Genetics

Modifiable

• Arterial Hypertension

• Diabetes Mellitus

• Dyslipidemia

• Cigarette smoking

• Alcohol consumption

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 Review of Literature

• Obesity

• Physical inactivity

• Transient Ischaemic Attack

• Prior stroke

• Asymptomatic carotid bruit/stenosis

• Cardiac disease

• Atherogenic host factors

• Increased Fibrinogen

• Atherogenic host factors

• Elevated homocysteine

• Low serum folate

• Elevated anticardiolipin antibodies

• Oral contraceptives

• Dietary factors

More recent data from the Interheart45 and Interstroke1 studies conducted

in 22 countries including India, identified 10 major risk factors for stroke that

contribute to 90% of stroke in these countries. These are history of

hypertension, smoking, waist-to-hip ratio (abdominal obesity), diet risk score,

regular physical activity, diabetes mellitus, alcohol intake, psychosocial stress

and depression, cardiac causes, and ratio of apolipoproteins B to A1. These

risk factors were all significant for ischaemic stroke, whereas hypertension,

smoking, waist-to-hip ratio, diet, and alcohol intake were significant risk factors

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 Review of Literature

for intracerebral haemorrhagic stroke. Table 2 explains the risk factors for

stroke in the study .1

Table 2: Inter-heart45 and Inter-stroke1 studies: Top ten risk factors for

stroke:

INTERHEART (acute
INTERSTROKE (all
myocardial infraction;
stroke; 3000 cases,
15152 cases, 14820
3000controls)
controls)
Hypertension 34.6% (30.4-39.1) 17.9% (15.7-20.4)
Smoking 18.9% (15.3-23.1) 35.7% (32.5-39.1)
Waist – to – hip ratio
26.5% (18.8-36.0) 20.1% (15.3-26.0)
(abdominal obesity)
Diet
Diet risk score
18.8% (11.2-29.7) -
Fruits and vegetables
- 13.7% (9.9-18.6)
daily
Regular physical activity 28.5% (14.5-48.5) 12.2% (5.5-25.1)
Diabetes 5.0% (2.6-9.5) 9.9% (8.5-11.5)
Alcohol intake 3.8% (0.9-14.5) 6.7% (2.0-20.2)
Psychological factors
All psychological factors - 32.5% (25.1-40.8)
Psychological stress 4.6% (2.1-9.6) -
Depression 5.2% (2.7-9.8) -
Cardiac causes 6.7% (4.8-9.1) -
Ratio of apolipoproteins
24.9% (15.7-37.1) 49.2% (43.8-54.5)
B to A1

Non-modifiable Risk Factor

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The incidence of stroke increases dramatically with advancing age.

Above 55 years, the incidence doubles each decade. Half of all strokes occur in

people older than 70-75 years. Men are more likely to have a stroke than

women: the male/female sex ratio for India is 7:1. 46 This may be due to

protective effects of female sex hormones and differences in risk factors such

as smoking and drinking which are more prevalent among men in India

compared with women.47 The mean age of onset of stroke for men in India

ranges from 63-65 years for men and 57-68 years for women. 34 A study by Ralf

Sacco et al in 1995 showed that blacks have higher rates of intracranial

atherosclerotic occlusive disease compared with whites.48 Although heredity

plays only a minor role in the pathogenesis of stroke, an increased risk is seen

among first-degree relatives with a family history of stroke.

Modifiable Risk Factors

Hypertension

Arterial hypertension predisposes to both ischemic and haemorrhagic

strokes. Hypertension accelerates atherosclerosis and heart disease increasing

the relative risk of stroke to four folds compared to normotensives. Self-reported

history of hypertension was the strongest risk factor for stroke, and was

stronger for intracerebral haemorrhagic stroke than for ischaemic stroke.1

Diabetes Mellitus

Diabetes increases the risk of ischemic stroke two to four folds compared

to those without diabetes. This is due to accelerated cerebrovascular

atherosclerosis, cardiac embolism or rheological abnormalities. Self-reported

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 Review of Literature

history of diabetes mellitus was associated with an increased risk of all stroke

and ischaemic stroke, but not intracerebral haemorrhagic stroke.1

Dyslipidaemia

In INTERSTROKE study1, they found that increased concentration of total

cholesterol was not associated with risk of ischaemic stroke, but was

associated with reduced risk of intracerebral haemorrhagic stroke. Increased

concentration of HDL cholesterol was associated with a reduced risk of

ischaemic stroke, but an increased risk of intracerebral haemorrhagic stroke,

whereas increased concentration of ApoA1 was associated with a reduced risk

of ischaemic stroke, but was not associated with risk of intracerebral

haemorrhagic stroke. Increased concentration of non-HDL cholesterol was not

associated with risk of ischaemic stroke, but was associated with reduced risk

of intracerebral haemorrhagic stroke, whereas increased concentration of

apolipoprotein B was associated with increased risk of ischaemic stroke, but

was not associated with risk of intracerebral haemorrhagic stroke. Ratio of non-

HDL to HDL cholesterol was associated with increased risk of ischaemic stroke

but reduced risk of intracerebral haemorrhagic stroke. Ratio of apolipoprotein B

(ApoB) to apolipoprotein A1 (ApoA1) was a stronger predictor of ischaemic

stroke than was ratio of non-HDL to HDL cholesterol.

Low cholesterol has been implicated in intracranial haemorrhage, possibly

due to an alteration in cell membrane leading to weakening of the endothelium.

Cardiac Disease

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 Review of Literature

Coronary heart disease and stroke have shared risk factors and hence go

hand in hand. Coronary heart disease may increase risk of stroke by causing

cerebral embolism and pump failure. Atrial fibrillation is an independent risk

49
factor for ischemic stroke, with an age-adjusted risk ratio of 4.8. For patients

with both coronary artery disease and atrial fibrillation, the risk of stroke doubles

in men, but increases almost 5-fold in women.50

Cardioembolism is an important cause of ischemic stroke worldwide. 51In

high income countries, it accounts for 15-25% of all ischemic strokes, mostly as

a consequence of atrial fibrillation, aortic arch disease and myocardial

infarction. Limited data from India supports a similar frequency of

cardioembolism, but the causes appears to be very different. Key differences

52 53
include rheumatic heart disease, and idiopathic and dilated cardiomyopathy

reported to be a frequent cause of premature stroke in young patients in many

countries including south asia.54-57

Smoking

Cigarette smoking increases the risk of stroke in men and women of all

age groups by enhancing atherogenesis, triggering cardiac arrhythmias, arterial

thrombosis and spasm. In INTERSTROKE study, 1 they found a dose-response

association for number of cigarettes smoked per day, which was more marked

for ischaemic stroke than for intracerebral haemorrhagic stroke. Smoking was a

strong risk factor in all regions and in all patient subgroups. By contrast with the
45
INTERHEART study, they noted that former smoking conferred no hazard,

but instead was associated with reduced risk compared with never smoking;

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 Review of Literature

this finding has also been reported by another large study. 58 Even if this

apparent reduced risk is not real, the finding suggests that risk rapidly reduces

after stopping smoking, indicating that smoking cessation is an essential

component for any stroke prevention programme.

Alcohol

There is a J shaped association between alcohol consumption and

ischemic stroke. Moderate consumption of alcohol elevates HDL and is

beneficial while heavy drinking increases the risk of ischemic stroke. A history

of alcohol intake of 1–30 drinks per month was associated with a reduced risk

of ischaemic stroke, whereas consumption of more than 30 drinks per month or

binge drinking were associated with increased risk compared with never or

former alcohol intake.1 For intracerebral haemorrhagic stroke, risk increased

with alcohol intake.1

Smoking and drinking are more prevalent among men in India compared

with women (Das + Banerjee 2008). 47

Obesity

In INTERSTROKE study1 assessment of anthropometrical factors showed

that body-mass index was not associated with stroke. Conversely, waist-to-hip

ratio was associated with increased risk of all stroke, and both ischaemic and

intracerebral haemorrhagic stroke. In participants who completed both supine

and standing measurements for waist-to-hip ratio, they recorded a strong

correlation between sitting and standing measurements.

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 Review of Literature

Fibrinogen

Fibrinogen is an independent risk factor for ischemic stroke and increased

levels correlate with other risk factors like smoking, Hypertension, Diabetes

mellitus, obesity, haematocrit etc.59

Homocysteine

Elevated plasma levels of homocysteine along with decreased folate

levels are associated with increased incidence of Coronary heart disease and
60
ischemic stroke particularly in Black populations. Folate supplementation has

been reported to be associated with a reduced risk of stroke in a meta-analysis.

61, 62

Oral Contraceptive Pills (OCP)

Oral Contraceptive Pills containing high dose of estrogen increased the

relative risk of stroke particularly when associated with other risk factors. Newer

agents with lower doses of estrogen and progesterone have reduced the risk of

Oral Contraceptive Pills related cerebral infarction to insignificant levels.

Sedentary Life Style

Lack of physical activity has far reaching effects on the risk factors for

stroke. Blood pressure, Impaired Glucose Tolerance, LDL, platelet

aggregability, insulin resistance are all increased along with a decrease in HDL

cholesterol levels. Regular physical activity is protective of stroke.61

INTERSTROKE STUDY investigators recorded a consistent association

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between physical activity and risk of ischaemic and haemorrhagic stroke, with a

larger population attributable risk (about 29%) than was reported in

INTERHEART 45 for acute myocardial infarction (12%).1

Dietary factors

The relation between excessive salt intake and hypertension was

63
established by INTERSALT study, but relation between salt intake and

stroke is variable.61 In countries with high salt intake there is a clear association,

whereas in countries with low sodium intake it is variable. 61 Other dietary

factors, such as fruit and vegetable consumption, are associated with a reduced

risk of stroke and excessive fried foods and fat intake with an increased risk.61,64

It is also important to realise that specific infections in India may also

contribute to stroke. These infections include malaria, neurocysticercosis,

leptospirosis, and viral haemorrhagic fevers. Conditions such as sickle cell

anaemia, and snake bites are other prevalent disorders that can produce a

stroke-like picture owing to intra-cerebral haemorrhage.65 Cerebral venous sinus

thrombosis is a common cause of stroke among women in India, especially

during postpartum period.66

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CLINICALSYNDROMES OF CEREBRAL ISCHAEMIA

Transient ischaemic attack (TIA) 67

Transient ischaemic attack acts as a warning signal of impending stroke. It

is known that 80% of ischemic strokes occur in the carotid artery territory and

20% in the vertebrobasillar territory.1/3rd of untreated patients of Transient

ischaemic attack develop stroke within 5 years. Transient ischaemic attack is a

transient focal neurological deficit of sudden onset due to ischemia of the brain,

retina or cochlea lasting less than 24 hours. The episode is followed by

complete recovery with no residual deficits.

Carotid circulation

Transient ischaemic attack may cause ipsilateral amaurosis fugax,

contralateral sensory or motor dysfunction, aphasia, contralateral homonymous

hemianopia or a combination of the above.

In the vertebrobasillar territory, Transient ischaemic attack may present as:

 Weakness, clumsiness which may be unilateral, bilateral or shifting.

 Sensory loss or paraesthesia, which may be bilateral, shifting or crossed.

 Homonymous hemianopia or binocular visual loss.

 Combinations of vertigo, diplopia, dysphagia, dysarthria and ataxia.

Carotid artery occlusions

Carotid artery occlusions present like Middle Cerebral Artery territory

infarctions, the only distinguishing feature being amaurosis fugax. Amaurosis

fugax is a transient visual loss in one eye lasting for 1-5 minutes and rarely

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 Review of Literature

more than 30minutes.Usually vision is fully restored although some patients

may be left with permanent visual loss due to retinal infarction.

Anterior choroidal artery occlusion

Complete occlusion of the anterior choroidal artery results in

contralateral hemiplegia, hemianaesthesia and homonymous hemianopia. But

this picture is rarely seen as this territory has extensive collaterals from the

Middle Cerebral Artery, Posterior Cerebral Artery and posterior communicating

artery.

Anterior cerebral artery occlusion

Acute cerebral infarcts in the Anterior Cerebral Artery territory are

uncommon and constitute less than 3% of ischaemic strokes. Occlusion of the

main trunk causes flaccid paralysis of the contralateral leg with cortical sensory

loss. If the recurrent artery of Heubner is involved, then upper motor neuron

palsy facial palsy and a spastic arm results on the contralateral side. When the

paracentral lobules are involved, voluntary control of micturition is often

impaired with incontinence of urine. Intellectual deficit and memory disturbance

may occur due to damage to frontotemporal and frontoparietal fibres in the

cingulate gyrus. Other features that may be seen with Anterior Cerebral Artery

occlusions are abulia, akinetic mutism (bilateral mesiofrontal damage) and

transcortical motor aphasia (with dominant hemisphere infarcts). An anterior

disconnection syndrome with apraxia of the left arm may result due to

involvement of the anterior part of the corpus callosum.

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 Review of Literature

Middle cerebral artery occlusion

Occlusion of the main trunk of the Middle Cerebral Artery results in

massive infarction of the bulk of the hemisphere with considerable oedema

which may cause coma and death.

Flaccid weakness of the arm and face with involvement of the adjacent

leg area due to oedema is the usual clinical picture. Hemianaesthesia and

complete hemianopia may also be seen. Dominant hemisphere lesions are

accompanied by global dysphasia and non-dominant hemisphere lesions by

dyspraxia.

Occlusion of the lenticulostriate artery is the commonest type of stroke

encountered in clinical practice. Typical capsular stroke results in contralateral

spastic hemiplegia with facial nerve paresis of upper motor neuron type. No

sensory loss or visual field defect occurs. Bilateral corticobulbar fibre

involvement may cause symptoms of pseudobulbar palsy.

Occlusion of the precentral and central arteries of the dominant

hemisphere cause contralateral facio-brachial paralysis with motor aphasia.

Posterior parietal and superior temporal artery occlusion cause sensory aphasia

with or without mild weakness and cortical sensory loss of contralateral side. In

the non-dominant hemisphere terminal branch occlusions are akin to the

dominant hemisphere except that aphasia is replaced by apraxia.

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 Review of Literature

Posterior Cerebral Artery

The effects of occlusion of the main trunk of the Posterior Cerebral Artery

are variable as there are numerous anastomoses between the Posterior

Cerebral Artery and the Middle Cerebral Artery. Variable degrees of confusion

and memory deficits may be seen due to the involvement of the inferior medial

surface of the temporal lobe and the hippocampus. Contralateral

hemianaesthesia (all modalities) with visual field defects may be seen due to

occlusion of the thalamogeniculate arteries damaging the posterior limb of the

capsule and the visual radiation.

Involvement of the perforating vessels supplying the brainstem gives rise

to the crossed hemiplegia syndromes that are known by eponymous names.

Weber’s syndrome is caused by infarction in the distribution of the penetrating

branches of the Posterior Cerebral Artery affecting the cerebral peduncle

wherein the third nerve fasciculus and the pyramidal tract fibres are damaged.

This causes ipsilateral third nerve palsy (with pupillary involvement) with

contralateral hemiplegia involving face leg and arm.

Involvement of the supranuclear fibres in the medial cerebral peduncle

causes horizontal gaze palsy to the opposite side with contralateral hemiplegia.

This is called Foville’s syndrome. Benedickt’s syndrome results due to

involvement of the red nucleus, brachium pontis and third nerve fascicle; patient

presents with ipsilateral third nerve palsy and contralateral involuntary

movements. If the dorsal aspect of the red nucleus is involved, then Claude’s

syndrome with ipsilateral third nerve and contralateral cerebellar signs results.

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Parinaud’s syndrome is characterized by supranuclear paralysis of eye

elevation, defective convergence, convergence retraction nystagmus, light-near

dissociation, lid retraction and skew deviation.

Thalamic infarcts may cause various deficits of which pure sensory,

sensory-motor strokes and the syndrome of Dejerine-Roussy are remarkable.

Neuropsychological disturbances, emotional-facial paresis, visual field

defects and decreased consciousness are also known to occur.

Occlusion of the calcarine artery causes macular sparing hemianopia.

Incomplete lesions can cause a variety of incomplete hemianopias, but in all

cases the deficit will be absolutely congruous and will spare the macula.

Bilateral occlusion in the distal Posterior Cerebral Artery produces

cortical blindness wherein there is:

• Complete loss of all visual sensation.

• Loss of reflex lid closure to threat.

• Normal pupillary light reactions.

• Normal retina and full extraocular eye movements.

In some cases the patient may be unaware of the blindness and may

even deny it. This is known as Anton’s syndrome. If bilateral visual

association areas are involved a distinct clinical picture known as Balint’s

syndrome results.

This includes optic ataxia (failure to grasp or touch objects under visual

guidance, ocular ataxia (inability to direct eyes to a precise point in the visual

field) and visual inattention affecting the periphery of the visual field. This

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 Review of Literature

syndrome results due to watershed infarcts between the Middle Cerebral Artery

and Posterior Cerebral Artery territories as occurs after a cardiac arrest.

Vertebral artery and branch occlusions

Occlusion of the vertebral artery or the posterior inferior cerebellar artery

causes the syndrome of Wallenberg (described in 1895).This is produced by a

wedge of infarction involving the lateral medulla posterior to the inferior olivary

nucleus. Patient presents with vertigo, sensory loss of the ipsilateral aspect of

face and contralateral limbs, diplopia, hoarseness of voice, dysarthria,

dysphagia and ipsilateral Horner’s syndrome. Occasionally occlusion of the

vertebral artery or its medial branches results in the Medial medullary syndrome

with infarction of the pyramid leading to contralateral hemiparesis sparing the

face.

Basillar artery occlusion

Complete occlusion of the basilar artery causes bilateral long tract signs

(sensory and motor) with variable cerebellar, cranial nerve and other segmental

abnormalities of the brainstem. The patient is often comatose because of the

involvement of the reticular activating system (RAS). If the reticular activating

system is spared then a ‘locked-in’ or ‘deafferented’ state may result wherein

consciousness and somatosensory pathways are spared. The corticobulbar and

corticospinal tracts are completely interrupted with vertical gaze and blinking

being the only movements possible.

Occlusion of the superior cerebellar artery causes ipsilateral cerebellar

ataxia, nausea, vomiting, pseudobulbar speech and loss of pain and

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temperature on the contralateral side. The anterior cerebellar artery has a

variable extent of infarction.

Lacunar strokes

Lacunar strokes have varied presentations with around 20 described

syndromes.

The four common ones are:

 Pure motor hemiplegia: involving the posterior limb of the internal

capsule, corona radiata or the base of pons

 Pure sensory stroke: involving the ventrolateral thalamus

 Ataxic hemiparesis: involving base of pons

 Dysarthria-clumsy hand syndrome: involving genu of Internal Capsule or

base of pons

Multiple lacunar infarcts involving the corticospinal and corticobulbar tracts

present with pseudobulbar palsy and are the commonest cause of this

syndrome.

CLINICALPRESENTATION OF PRIMARY INTRACEREBRAL

HEMORRHAGE

Primary intracerebal haemorrhage results predominantly due to chronic

hypertension and degenerative changes in the cerebral arteries. Unlike

ischemic strokes, which commonly occur during sleep, most hypertensive-

atherosclerotic intracerebral haemorrhage, begin during wakefulness, often

associated with exertion. Sudden severe headache sets in, heralding the onset

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of stroke, followed within minutes to hours by neurologic signs. The nature and

severity of signs reflect the site and extent of bleeding.

Systemic examination may disclose hypertension, cardiac enlargement

or evidence of atherosclerotic disease.

Table 2: Characteristics of Primary intracerebal haemorrhage at common sites
68

Motor-sensory Gaze
Site Headache Consciousness
Signs preference

Ipsilateral to
Basal ganglia- Contralateral Eyes deviate
bleed,
Internal hemiplegia, towards Coma frequent
Generally
capsule bleed Convulsions lesion
severe

Contralateral
Eyes deviate
hemianopia Drowsy to
Either or both down and
Thalamic Often coma with
sides Moderate contralateral
hemisensory large lesions
to lesion
defect

Bilateral
Stertorous
lateral
breathing, Coma within
Catalysmic
Pontine Bilateral gaze palsy, seconds to
Global
posturing Pin minutes
Ocular
point pupils, bobbing

Ipsilateral Late stupor or

Weakness coma, implies
Cerebellar incoordination,
Ipsilateral to Ipsilateral brainstem
Dysarthria,
bleed, Occipital conjugate compression
Facial
gaze palsy
weakness

Lobar Haemorrhage

These occur in the peripheral distribution in the white matter of the

cerebral or cerebellar hemispheres. They are usually smaller and produce

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fewer acute or permanent neurologic abnormalities than the deep hematomas.

Large bleeds have a catastrophic onset and progress with poor prognosis.

Sex Differences in Stroke Symptom Presentation

A prospective observational study of patients with validated stroke in

community emergency departments found that women were more likely than

men to present with nontraditional stroke symptoms such as pain, a change in

level of consciousness, nonspecific, or unclassifiable neurological symptoms

(28% versus 19%).69 Men were more likely than women to report traditional

stroke symptoms such as hemiparesis or imbalance.69 Additional clinical

research is needed to identify barriers to care in women and improve access for

all patients with acute stroke.

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 Review of Literature

DIAGNOSIS

Early recognition and diagnosis of stroke using validated tools outside

hospital environment can help save life and limit disability. 70 Specifically the

Face Arm Speech and Time (FAST) test is a lay approach to diagnose stroke

and is widely used to raise awareness about early recognition of stroke among

the public in developed countries.71

Computerised Tomographic scanning (CT scan)

CT scan is a simple and non-invasive way of differentiating between

ischemic and haemorrhagic infarcts. Primary intracerebal haemorrhage appears

at once on CT scan, as a well demarcated, high density lesion. Around 60% of

CT scans obtained within the first few hours of cerebral infarction are normal.

Some of the early CT features of ischemic stroke are loss of gray-white matter

differentiation, sulcal effacement, effacement of the Sylvian fissure and

obscuration of the Lentiform nucleus. The dense middle cerebral artery sign

refers to the hyperdense horizontal part of the Middle Cerebral Artery, which is

seen before the infarction becomes visible. CT scan also picks up supratentorial

lacunar infarcts, though posterior fossa and cortical infarcts may be missed.72

Primary intracerebal haemorrhage may be visualized immediately on CT

scan as a well demarcated high density, round or oval area, with or without

rupture into the ventricles or on to the surface of the brain. With large

haemorrhages, CT scan may also show cerebral herniation or hydrocephalus.

With time the lesion becomes less dense, isodense and in some cases

hypodense, appearing like an ischemic infarct after some time. Contrast

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 Review of Literature

enhanced CT scans increase the specificity of the scan by enhancing subacute

infarcts.

Magnetic Resonance Imaging (MRI)

MRI is superior to CT scan in identifying ischemic infarcts, particularly

with posterior fossa infarcts. Brainstem infarcts are likely to be better seen with

MRI as are cerebral hemisphere lacunar infarcts, especially on T2 weighted

images. Ischemic changes appear earlier on MRI as compared to CT. However

MRI is not as sensitive as CT in picking up haemorrhages and is more

expensive.

Other Investigations

Imaging of the extracranial arteries should be undertaken only in patients

with transient ischemic attack or minor stroke in which carotid endarterectomy is

contemplated. It can be done by Doppler ultrasonogram or carotid angiogram.

With the advent of Duplex scans, carotid angiograms are being used more

selectively Carotid Angiograms are mainly indicated in detecting symptomatic

carotid artery stenosis when surgical treatment is planned. Echocardiographic

evaluation is done to identify cardiac sources of embolism.

MR spectroscopy, Positron emission tomographic scan, Single photon

emission tomography are used as research tools and have no place in the

routine work up of stroke. MRI has not come into routine use in the diagnosis of

stroke because of financial constraints and the claustrophobia associated with

the procedure.

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 Review of Literature

Treatment of stroke

The treatment of stroke has in the past held a low priority for most medical

institutions and physicians. However, increasing awareness about the impact of

stroke on individual patients, their families and society as a whole has led to its

being identified as a priority area for improving services and research. This has

led to various randomized trials and systematic reviews of medical and surgical

treatments as well as primary and secondary prevention strategies.73

The management of stroke consists of two specific areas:

• Specific management of stroke

• General and supportive care

Specific Management of Stroke

Acute ischaemic infarct

During focal brain ischemia, there are two stages of neuronal failure:

• The reversible stage of electrical failure seen in the ischemic penumbra

region.

• The irreversible stage of cellular homeostatic failure seen in the infarcted

area.

The aim of early treatment is to salvage the viable tissue in the ischemic

penumbra region by:

• Early reperfusion by thrombolysis and restoration of normal flow.

• Neuroprotection by administering agents which could protect these

potentially viable neurons from further damage.

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 Review of Literature

Early treatment of stroke employs these strategies to save viable tissue.

However the duration of viability of ischemic tissue is not known and it is likely

that the time window for intervention will vary from one individual to another.

Thrombolysed patients are expected to have early neurological recovery,

reduced hospital stay and better functional outcomes at 3 months post stroke. 74

Symptomatic intra cranial haemorrhage within 36hours of onset of stroke

occurred in 6.4% of patients treated with tissue plasminogen activator (r-tPA)

but only 0.6% of patients given placebo (p<0.001). Mortality at three months

was 17% in the tissue plasminogen activator (r-tPA) group and 21% in the

placebo group (p<0.3). Early treatment within 3 hours of onset of stroke was

shown to reduce the risk of intra cranial haemorrhage and increase the potential

for recovery.73

Suggested guidelines for the use of intravenous tissue plasminogen

activator (r-tPA) in ischemic stroke:

• Intravenous tissue plasminogen activator (r-tPA) should be considered in

all patients with a proven ischemic stroke presenting within three hours

of onset.

• Recommended dose is 0.9 mg/kg, up to a maximum of 90 mg, the first

10% as bolus and the rest as an infusion over 60 minutes.

• Thrombolysis should be avoided in cases where the CT scan suggests

early changes of major infarction (e.g. Sulcal effacement, mass effect or

oedema).

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• Thrombolytic therapy should only be administered by physicians with

expertise in stroke medicine, who have access to a suitable stroke

service, with facilities for identifying and managing haemorrhagic

complications.

• Caution is advised before giving tissue plasminogen activator (r-tPA) to

patients with severe stroke (NIHSS score >22).

• Recommended that treatment and adverse effects discussed with patient

and family before treatment.

Exclusion criteria for thrombolysis:

• Use of oral anticoagulants or International Normalized Ratio >1.7

• Use of heparin in preceding 48 hours.

• Prolonged major surgery within previous 14 days.

• Pre-treatment systolic blood pressure > 185 mm of Hg or

diastolic>110mm of Hg.

• Rapidly improving neurological condition or mild isolated neurological

deficits.

• Previous intracranial haemorrhage.

• Blood glucose greater than 400 mg/dl or less than 50 mg/dl.

• Seizure at stroke onset.

• Gastrointestinal or urinary bleeding within the last 21 days.

• Recent Acute MI.

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 Review of Literature

Anticoagulants

Anticoagulation started on the first day or two of stroke, may reduce the

risk of deep vein thrombosis and pulmonary embolism. Anticoagulants are

beneficial in case of evolving ischemic strokes established by CT scan, which is

likely to be due to progressive thromboembolism. Warfarin is effective in the

secondary prevention of stroke in patients with atrial fibrillation. There is

presently no consensus on anticoagulation in patients with potential

cardioembolic source like mitral valve disease without AF; and in such cases

treatment is individualized.

Secondary prevention

Optimal medical therapy that includes antiplatelet therapy, statin therapy,

and risk factor modification, is recommended for all patients with carotid artery

stenosis and Transient ischemic attack or stroke as a secondary measure of

prevention.75 For patients with non-cardioembolic or ischemic stroke or

Transient ischemic attack, secondary prevention includes the use of antiplatelet

agents rather than oral anticoagulants to reduce the risk of recurrent stroke and

other cardiovascular events. Aspirin (50 mg/d to 325 mg/d) monotherapy,

combination of aspirin 25 mg and extended-release dipyridamole 200 mg twice

daily, and clopidogrel 75 mg monotherapy are considered acceptable options

for initial therapy. It is recommended that the selection of an antiplatelet agent

should be individualized on the basis of patient risk factor profiles, cost,

tolerance, and other clinical characteristics.75

Neuroprotective agents

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 Review of Literature

Various agents have been in use for neuroprotection during the last

decade. NMDA antagonists, Antioxidants, GABA receptor agonists, Adenosine

analogues, and Apoptosis inhibitors are some of them. However, there is no

convincing evidence to support the routine use of any of these.

Acute Management of Haemorrhagic Stroke

Various specific treatments designed to reduce Intra cranial pressure are

often used for Primary intracerebral haemorrhage .This includes osmotic agents

like mannitol, urea or glycerol, steroids, hyperventilation etc. However there is

no convincing evidence that these treatments improve outcome. Every attempt

should be made to identify and reverse any clotting abnormality e.g. in patients

on anticoagulants, while keeping the original indication for anticoagulation in

mind.

Surgical Treatment of Intracranial Haemorrhage

In case of supratentorial Primary intracerebral haemorrhage, studies

have shown that open surgical drainage via craniotomy is harmful. Safer

surgical techniques like stereotactic aspiration have better outcome.

Surgical treatment of infratentorial Primary intracerebral haemorrhage:

Surgical treatment should always be considered in a patient with

progressively deteriorating conscious levels or in coma, in whom other

exacerbating causes have been excluded. The choice is between hematoma

evacuation and ventricular decompression. Once brainstem reflexes have been

absent for several hours, death is inevitable.

General and Supportive Care

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When a patient of stroke is admitted, a full assessment should be done,

to identify existing problems and to anticipate future ones, so that a problem

oriented management plan can be constructed. Some of the common problems

are as follows:

Airway and Breathing

In patients with impaired consciousness, upper airway obstruction should

be excluded. Stroke itself may cause various abnormal breathing patterns like

periodic respiration and hyperventilation. Significant hypoxia however should

prompt a search for possible causes like pulmonary oedema, pulmonary

embolism or infection.

Circulation

Cerebral auto-regulation is disturbed after stroke and cerebral blood flow

becomes directly dependent on systemic blood pressure. Thus the

pharmacological lowering of raised blood pressure should be attempted with

caution and is done only when there are features of accelerated hypertension,

hypertensive encephalopathy or aortic dissection.73

Hypotension is relatively uncommon in stroke and is usually secondary

to coexistent heart disease, dehydration or sepsis and when present should be

aggressively corrected due to its potential danger.

Increased Intracranial Pressure

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 Review of Literature

Increased Intracranial Pressure rises very rapidly after haemorrhagic

strokes, due to the space occupying effects, while it takes at least 48 hours and

often longer to manifest in case of ischemic strokes. Various treatments like

mannitol, hyperventilation and decompressive surgery have been employed in

clinical practice although their efficacy has not been established by randomized

trials.

Swallowing, Hydration and Nutrition

All stroke patients should have a bedside swallowing assessment as

dysphagia and poor nutrition are common. The gag reflex is unreliable indicator

of swallowing ability and should not be used for assessment. In patients with

dysphagia fluids should be prescribed either intravenously or via nasogastric

tube. Percutaneous endoscopic gastrostomy is the best option when prolonged

tube feeding is necessary.

Glycaemic Control

Hypoglycaemia should be excluded on admission as it may mimic stroke,

and delay in its correction may lead to death or permanent disability.

Hyperglycaemia is associated with poor outcomes and should be treated.

Pyrexia

Raised temperature may exacerbate ischemic cerebral damage and is

associated with a poor outcome. Hence it should be reduced with simple

measures like tepid sponging. An attempt should be made to identify the cause

of pyrexia which may be due to stroke itself, endocarditis, chest or urinary

infection or venous thromboembolism.

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Pressure Sores

Decubitus ulcer is a preventable complication and its prevention depends on

expert nursing care and the judicious use of specialized cushions and

mattresses.

Bladder Management

Incontinence of urine is common in the first few days and is due to impaired

sphincter control, immobility, communication problems, constipation, pre-

existing prostatic or gynaecological problems, inadequate nursing, infection,

confusion and impaired consciousness. Urinary retention is common in men

and should be managed with external or internal urinary devices as necessary.

Venous Thromboembolism Prophylaxis

The two strategies for prevention of deep vein thrombosis are physical

measures (early mobilization, compression stockings) and antithrombotic drug

therapy. Early mobilization is recommended where possible and compression

stockings for patients at high risk.

Epileptic Seizures

Seizures occur in about 5% of patients within two weeks of stroke. A

search for precipitating factors should be undertaken and seizures managed

like other forms of secondary epilepsy with anticonvulsants.

Stroke Prevention Strategies

Primary prevention is aimed at detecting and controlling the modifiable risk

factors like Hypertension, diabetes mellitus, hyperlipidaemia etc. Antiplatelet

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therapy with aspirin, dipyridamole or a combination of the two, or clopidogrel

forms the mainstay of secondary stroke prevention. Anticoagulation is

recommended in patients with cardiac sources of emboli with an INR in the

range of 2-3 with frequent monitoring of the patient.76

Carotid Endarterectomy

Carotid Endarterectomy is indicated in transient ischemic attack or minor

strokes with stenosis of greater than 60% of carotid lumen diameter. Carotid

Endarterectomy was found to reduce the absolute risk of stroke by 17% and for

major stroke and death by 10%.

Indications for Carotid Endarterectomy

Degree of stenosis by NASCET criteria Recommendation

A. Symptomatic disease
70-90% Carotid Endarterectomy.
50-69% Carotid Endarterectomy if in high-risk
group (men and patients with
hemispheric TIA or strokes).
Medical management (risk factor
<50% control +aspirin 50-325 mg/day).

B. Asymptomatic disease
>60% Consider Carotid Endarterectomy.
NASCET – North-American Symptomatic Carotid Endarterectomy Trial

PREDICTORS OF STROKE OUTCOME

Stroke is a heterogeneous disease in which outcome is influenced by

many factors. Demographic variables, risk factors, clinical examination findings,

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laboratory test results, and imaging studies all provide important insight

regarding outcome.

Demographic Factors

Age negatively influences outcome in stroke, this can be explained by

the high frequency of secondary complications among elderly stroke patients

and the high incidence of other systemic illnesses that preclude recovery. The

only situation in which advanced age may be protective is in a setting of large

Middle Cerebral Artery stroke with mass effect, wherein age related brain

atrophy provides additional intracranial volume for space-occupying oedema.

Gender, Race and Ethnicity

Data vary as to whether there is a difference in stroke severity between

men and women. Some studies indicated that women suffer more severe
14, 77
strokes than men, whereas others found no significant difference between

the sexes.78, 79 However, most researchers agree that disability, mortality, and

case fatality are greater in women than men, which are confounded by the

overall older age of women at stroke onset.16 As of 2005, stroke accounted for 1

of every 17 deaths in the United States, with women accounting for 60% of

stroke deaths (1). Age-adjusted studies indicate a slightly lower mortality rate

for women overall, 16 although over the age of 85 years, women still have a 15%

higher stroke mortality than age-matched men.80 Multiple studies indicate that

the excess of women who die from stroke is increasing dramatically.16, 80

Various studies also have looked at case fatality rates by sex and found

no significant difference between men and women or that women had slightly

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higher rates.16 A compilation of multiple case fatality studies showed that

women have a higher rate of fatality in 26 out of 31 studies that followed patient

outcome for 28 or 30 days post-stroke. 14 The International Stroke Trial found

higher case fatality rates for women at 14 days and at 6 months post-stroke, but

when differences such as age and comorbidities were normalized between the

sexes, the higher fatality in women was negated at 6 months post-stroke. 81 The

Women’s Health Organization MONICA Project performed a 28-day monitoring

of stroke patients and found women to be equivalent or higher than men in case

fatality rates.16 A recent Framingham Heart Study found no significant difference

in case fatality rates for 30-, 90-, and 180-day studies. 78 Baseline differences

between men and women (eg, age, comorbidities, severity, and pre-stroke

disability) cause much of the excess of mortality in women. However, even

when controlling for these factors, women continue to have poorer functional

outcomes after stroke.

Women are more likely to be severely disabled at the time of discharge

compared to men (36.1 versus 24.2%).77 Women are less likely than men to be
83
discharged home after a stroke admission (40.9 versus 50.6%), and are more

likely to be discharged to long-term care upon hospital discharge (10 versus

5%).84

Cerebrovascular Risk Factors

The two major risk factors that influence outcome are previous stroke

and atrial fibrillation. Previous stroke is associated with higher likelihood of

death or dependence due to a lower pre-stroke level of function and more

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advanced cerebrovascular disease. Strokes in patients with atrial fibrillation are

usually more sever, more disabling and associated with a higher mortality.85

Clinical presentation

Specific clinical examination findings are useful in determining stroke

outcome. Several stroke severity scores have been developed based on clinical

parameters that accurately predict outcome. These scores are most accurate in

moderately severe strokes and less so in severe or mild strokes.

The Oxfordshire Community Stroke Project (OCSP), ischaemic stroke

classification is also a widely used acute stroke scale that differentiates strokes

into 4 groups.

• TACI- Total anterior circulation infarct

• PACI - Partial anterior circulation infarct

• POCI- Posterior circulation infarct

• LACI- Lacunar infarct

TACI group patients do not recover mobility quickly and are more often

dependent at discharge.

Table 4: Outcome predicted by clinical features and stroke severity scales

Good
Baseline factors Poor outcome
outcome
Normal level of Decreased level of
Admission clinical features
consciousness consciousness
Temperature <37.5 ºC >38.5 ºC
Severe blood pressure
Blood pressure Normal
elevation
OSCP classification LACI TACI
TOAST classification Small vessel disease Large vessel disease

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MRS SCORE 1 OR 2 3 TO 5
TACI – total anterior circulation infarct, PACI- partial anterior circulation infarct, POCI – posterior circulation
infarct, LACI – Lacunar infarct, OSCP- Oxfordshire Community Stroke Project, MRS - modified-Rankin
scale, TOAST - Trial of Org 10172 in Acute Stroke Treatment

86
Hart et al screened in the early to mid-1970s, 7052 men and 8354

women from the Renfrew/Paisley prospective cohort study in Scotland when

aged 45 to 64 years. Risk factors measured included blood pressure, blood

cholesterol and glucose, respiratory function, cardiothoracic ratio, smoking

habit, height, body mass index, age, pre-existing coronary heart disease, and

diabetes. These were related to stroke mortality over 20 years of follow-up.

Women’s stroke mortality rates were similar to men’s, unlike coronary heart

disease mortality, in which case women’s rates were lower than men’s.

Diastolic and systolic blood pressure, smoking, cardiothoracic ratio, pre-existing

coronary heart disease, and diabetes were positively related to stroke mortality

for men and women, while adjusted forced expiratory volume in 1 second and

height were negatively related. Cholesterol and body mass index were not

related to stroke mortality. Glucose in non-diabetics was positively related to

stroke mortality for women but not men, and there was evidence of a threshold

effect at the highest levels of glucose. Former smokers had mortality rates that

were similar to those of never-smokers. In sex-specific multivariate models,

most variables retained a statistically significant association with stroke

mortality, illustrating the multifactorial etiology of stroke.

83
Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV et al. performed a

population based cohort study using administrative databases on all 44 832,

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patients discharged from acute-care hospitals in Ontario between April 1993

and March 1996. Male stroke patients were more likely than female stroke

patients to have a history of ischemic heart disease (18.1% versus 15.3%,

respectively; P<0.001) and diabetes mellitus (20.1% versus 18.7%, respectively;

P<0.001), whereas female patients were more likely than male patients to have

hypertension (33.8% versus 30.0%, respectively; P<0.001) and atrial fibrillation

(12.9% versus 10.2%, respectively; P<0.001). There were no sex differences in

the usage of in-hospital rehabilitative services. Elderly men are more likely than

elderly women to receive aspirin and ticlodipine and equally like to receive

warfarin after a stroke. Despite these differences, elderly women have a better

1-year survival after a stroke.

87
ERMANCIA study was a prospective community-based study

performed in Martinique (French West Indies) from June 1, 1998, to May 31,

1999. The black at-risk population was approximately 360 000. Multiple sources

were used to identify hospitalized and non-hospitalized patients with first-ever

stroke. Five hundred eighty patients (285 men and 295 women; mean±SD age,

71.2±14 years) suffered from a first-ever in a lifetime stroke, yielding a crude

annual incidence of 164/100 000 per year (95% CI, 151 to 177). The rates

adjusted by age and sex to the French population (1999 census) and to the

European population were 202 (95% CI, 185 to 218) and 151 (95% CI, 139 to

164), respectively. Thirty-eight patients (6.5%) were not hospitalized during the

acute phase of the stroke; 92.8% had CT scan. Pathological types of strokes

were infarction (79.8%, including 23% of lacunar strokes), intracerebral

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 Review of Literature

haemorrhage (14.3%), subarachnoid haemorrhage (3.4%), and undetermined

(2.4%). The main risk factors for stroke were hypertension (69.1%) and

diabetes (29.5%). The 30-day case fatality rate was 19.3% (15.8% for cerebral

infarction and 37.3% for intracerebral haemorrhage).

88
Banerjee TK, Mukherjee CS, Sarkhel A. et al. conducted a

population based cluster survey conducted on 50.291 individuals in the city of

Calcutta. Incidentally, this was the first population-based study to report on the

nature of stroke in India. In this study, the age-adjusted prevalence and

incidence rates of stroke were lower than those reported from western

countries, but there were relatively more cases of intracerebral haemorrhage

than in those observed in European countries. Odds ratio for hypertension was

5.04 (95% CI 4.16 - 5.92) in women and 21.87 (95% CI 18.69–25.05) in men.

Diabetes mellitus had the OR 0.99 (95% CI 0.28–2.26) in women and 1.61

(95% CI 0.17–3.05) in men. Smoking in men had the odd’s ratio 2.91 (95% CI

1.57– 4.25). It was also observed that the age-specific incidence and

prevalence rates of stroke were higher among women, which was in contrast to

the other reports.

Worall et al. 89 performed a planned exploratory analysis of differences in

baseline characteristics and risk factors between women and men enrolled in

African-American Antiplatelet Stroke Prevention Study (AAASPS), a double-

blind, randomized, multicentre, controlled trial. Frequencies of vascular risk

factors and related conditions, medical therapies, stroke subtypes, and vascular

territories were compared between women and men by 1-way ANOVA and

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 Review of Literature

Fisher’s exact test where appropriate. A total of 1087 African American patients

(574 women, 513 men) enrolled between December 1995 and June 1999.

Women had higher rates of hypertension, diabetes, family history of stroke, and

no reported leisure exercise. Men had higher rates of smoking and heavy

alcohol use. Few differences were noted in proportions of stroke subtype or

proportions receiving preventive therapy.

90
Di Carlo et al. evaluated in a European Concerted Action involving 7

countries, 4499 patients hospitalized for first-in-a-lifetime stroke for

demographics, risk factors, clinical presentation, resource use, and 3-month

survival, disability (Barthel Index), and handicap (Rankin Scale). Overall, 2239

patients were males and 2260 females. Compared with males, female patients

were significantly older (mean age 74.5±12.5 versus 69.2±12.1 years), more

frequently institutionalized before stroke, and with a worse pre-stroke Rankin

score (all values P<0.001). History of hypertension (P=0.007) and atrial

fibrillation (P<0.001) were significantly more frequent in female stroke patients,

as were coma (P<0.001), paralysis (P<0.001), aphasia (P<0.001), swallowing

problems (P<0.005), and urinary incontinence (P<0.001) in the acute phase.

Brain imaging, Doppler examination, echocardiogram, and angiography were

significantly less frequently performed in female than male patients (all values

P<0.001). The frequency of carotid surgery was also significantly lower in

female patients (P<0.001). At the 3-month follow-up, after controlling for all

baseline and clinical variables, female sex was a significant predictor of

disability (odds ratio [OR], 1.41; 95% CI 1.10 to 1.81) and handicap (OR, 1.46;

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 Review of Literature

95% CI 1.14 to 1.86). No significant gender effect was observed on 3-month

survival.
77
Roquer J, Campello AR, Gomis M et al. from December 1995 to

January 2002, analysed 1581 patients with first-ever acute stroke, taking into

account sex, age, risk factors, clinical presentation, stroke subtype, treatment,

and outcome data. They concluded that sex determines some clear differences

in patients suffering a first-ever stroke. Women were, on average, 6 years older

than men. Mean age was higher in women than in men (P<0.001).

Hypertension (P=0.0027) and cardioembolic disease (P=0.0035) were

independent factors related to women. Alcohol overuse (P<0.001), smoking

(P<0.001), and vascular peripheral disease (P=0.031) were related to the male

sex. Women more often suffered aphasic disorders (P<0.001), visual field

disturbances (P<0.05), and dysphagia (P<0.01) than men. There were no

differences in haemorrhagic and ischemic strokes according to sex. Women

suffered more cardioembolic strokes (P<0.001); men suffered more

atherothrombotic (P<0.001) and lacunar strokes (P<0.05). Women who

survived remained more disabled than men (P<0.001).

Das SK, Banerjee TK, Biswas A, Roy T, Raut DK, Mukherjee CS,
7
Chaudhuri A, Hazra A, Roy J. et al. conducted a prospective community-

based study of stroke in Kolkata comprising 2-stage door-to-door survey of a

stratified randomly selected sample of the city population, conducted twice per

year for 2 successive years from March 2003 to February 2005. A total of

53,277 were screened of which 53 subjects (men, 21; women, 32) died within

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 Review of Literature

30 days. Thus, the 30-day case fatality rate was 41.08% (95% CI, 30.66 to

53.80) and greater for women (43.24%; 95% CI, 29.55 to 61.04) than men

(38.18%; 95% CI, 23.61 to 58.48). Most deaths (86%) occurred after 50 years of

age. They also concluded that age standardized prevalence and incidence rates

of stroke in this study are similar to or higher than many Western nations. The

overall case fatality rate is among the highest category of stroke fatality in the

world. The women have higher incidence and case fatality rates compared with

men.
91
Barret et al performed a prospective study of 505 patients with first-

ever ischemic stroke (the Ischemic Stroke Genetics Study), stroke subtype was

centrally adjudicated and infarcts were characterized by imaging. Deficits were

assessed by National Institutes of Health Stroke Scale and stroke symptoms

were assessed using a structured interview. Kappa statistics were generated to

assess agreement between the National Institutes of Health Stroke Scale and

the structured interview, and a χ2 test was used to assess agreement between

the National Institutes of Health Stroke Scale and the structured interview by

sex. Two hundred seventy-six patients (55%) were men and 229 (45%) were

women. Ages ranged from 19 to 94 years (median, 65 years). The mean (±SD)

National Institutes of Health Stroke

Scale score of 3.8 (±4.5) for men and 4.3 (±5.2) for women was similar

(P=.15). No sex difference was observed for the symptoms of numbness, visual

deficits, or language. Weakness occurred in a greater proportion of women

(69%) than men (59%) (P=.03). Stroke subtype did not differ significantly

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between sexes (P=.79). Infarct size and location were similar for each sex. The

association between symptoms and neurologic deficits did not differ by sex.
92
Gang Hu et al prospectively investigated the association of different

indicators of adiposity (body mass index [BMI] [calculated as weight in

kilograms divided by height in meters squared], waist circumference, and waist-

hip ratio) with total and type-specific stroke incidence among 49 996 Finnish

participants who were aged 25 to 74 years and free of coronary heart disease

and stroke at baseline. During a 19.5-year follow-up, 3228 people developed an

incident stroke event (674 haemorrhagic and 2554 ischemic). Compared with

normal-weight men (BMI, 18.5-24.9), the multivariate-adjusted (age, study year,

smoking, physical activity, educational level, family history of stroke, and

alcohol drinking) hazard ratios among lean (BMI, < 18.5), overweight (BMI,

25.0-29.9), and obese (BMI, > or = 30.0) men were 0.74 (95% confidence

interval [CI], 0.18-2.96), 1.23 (95% CI, 1.10-1.37), and 1.59 (95% CI, 1.37-1.83)

for total stroke, and 0.49 (95% CI, 0.07-3.50), 1.27 (95% CI, 1.12-1.44), and

1.70 (95% CI, 1.45-2.00) for ischemic stroke, respectively. Among women, the

corresponding hazard ratios were 1.87 (95% CI, 1.12-3.14), 1.08 (95% CI, 0.95-

1.22), and 1.30 (95% CI, 1.14-1.50) for total stroke, and 1.81 (95% CI, 0.97-

3.41), 1.11 (95% CI, 0.96-1.28), and 1.41 (95% CI, 1.21-1.64) for ischemic

stroke. Abdominal adiposity, defined as the highest quartile of waist

circumference or waist-hip ratio, was associated with a greater risk of total and

ischemic stroke in men but not in women.

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 Review of Literature

93
Gargano et al prospectively enrolled a total of 373 acute stroke

survivors discharged from 9 hospitals participating in a statewide stroke registry

in an outcomes study. Follow-up data, including the Barthel Index and Stroke-

Specific Quality of Life, were obtained from the survivor or a proxy by telephone

interview 90 days post discharge. The independent effects of sex on activities of

daily living independence (Barthel Index ≥95) and Stroke-Specific Quality of Life

scores, controlling for age, race, subtype, prestroke ambulatory status, and

other patient characteristics, were determined using adjusted odds ratios and

least-squares means, respectively. Twenty-five percent of the patients required

a proxy respondent. In adjusted models, females were less likely to achieve

activities of daily living independence (adjusted OR: 0.37, 95% CI: 0.19 to 0.87).

Females had lower least-squares means Stroke-Specific Quality of Life scores

in Physical Function (3.9 versus 4.2, P=0.02), Thinking (2.8 versus 3.4,

P<0.001), Language (4.3 versus 4.5, P=0.03), and Energy (2.6 versus 3.0,

P<0.01). Interactions between sex and prior stroke were found for Mood, Role

Function, and Summary Score, resulting in lower least-squares means for

females only among subjects without prior stroke.

79
Smith et al used a state-wide database, based on Get with the

Guidelines–Stroke (GGS), to explore gender differences in stroke in Colorado.

We analyse demographics, risk factors, lifestyles, treatments, and responses to

treatment. Of 126 data elements examined, statistically significant gender

differences were noted for 47 (37%). As compared to men, women in Colorado

were older and more significantly impacted by acute stroke. Risk factor profiles

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differed between the 2 genders, with men having a higher incidence of coronary

artery disease, dyslipidaemia, diabetes, carotid stenosis and tobacco smoking,

while women had a higher incidence of atrial fibrillation and hypertension. Lipids

were less aggressively treated and antithrombotics were less commonly used in

women. Overall, acute stroke treatment of women appeared “less aggressive”

than for men.

80
Lewsey et al performed a study in which all first hospitalizations for

stroke in Scotland (1986 to 2005) were identified using linked morbidity and

mortality data. Age-specific rate ratios (RRs) for comparing women with men for

both incidence and mortality were modelled with adjustment for study year and

socioeconomic deprivation. Logistic regression was used to model 30-day case-

fatality. Women had a lower incidence of first hospitalization than men and size

of effect varied with age (55 to 64 years, RR=0.65, 95% CI 0.63 to 0.66; 85

years, RR=0.94, 95% CI 0.91 to 0.96). Women aged 55 to 84 years had lower

mortality than men and again size of effect varied with age (65 to 74 years,

RR=0.79, 95% CI 0.76 to 0.81); 75 to 84 years, RR=0.94, 95% CI 0.92 to 0.95).

Conversely, women aged 85 years had 15% higher stroke mortality than men

(RR=1.15, 95% CI 1.12 to 1.18). Adjusted risk of death within 30 days was

significantly higher in women than men, and this difference increased over the

20-year period in all age groups (adjusted OR in 55 to 64 year olds 1.23, 95%

CI 1.14 to 1.33 in 1986 and 1.51, 95% CI 1.39 to 1.63 in 2005).

94
Stuart-Shor et al examined gender differences in the prevalence of

presenting and prodromal stroke symptoms among 1107 consecutive patients

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hospitalized with neurologist-confirmed acute ischemic stroke. Patient

demographics, clinical variables, and stroke symptoms were abstracted from

medical records by trained abstractors using standardized forms. Estimates

were age-standardized to the age distribution of men and women combined.

Presenting symptoms occurred within 24 hours of incident stroke admission;

prodromal symptoms occurred ≥24 hours of admission. Women were

significantly older (P<0.001), more likely to have cardioembolic stroke (P<0.01),

and less likely to receive aspirin (P=0.014) or statins (P<0.001). Thirty-five

percent of the sample (n=389) reported prodromal symptoms. Women were

more likely to have ≥1 somatic prodromal and presenting symptoms (P=0.03;

P=0.008), but did not differ from men on specific somatic symptoms. Women

did not differ from men in classic presenting stroke symptoms (P=0.89).
14
Peter Appelros et al searched PubMed, tables-of-contents, review

articles, and reference lists for community-based studies including information

on sex differences. In some areas, such as secular trends, ischemic subtypes

and stroke severity, non-community based studies were also reviewed.

Male/female ratios were calculated. They found 98 articles that contained

relevant sex-specific information, including 59 incidence studies from 19

countries and 5 continents. The mean age at first-ever stroke was 68.6 years

among men, and 72.9 years among women.

Male stroke incidence rate was 33% higher and stroke prevalence was

41% higher than the female, with large variations between age bands and

between populations. The incidence rates of brain infarction and intracerebral

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 Review of Literature

haemorrhage were higher among men, whereas the rate of subarachnoid

haemorrhage was higher among women, although this difference was not

statistically significant. Stroke tended to be more severe in women, with a 1-

month case fatality of 24.7% compared with 19.7% for men.

78
Petrea RE, Beiser AS, Seshadri S, Hayes MK, Kase CS, Wolf AP et al

followed the participants in the Framingham Original (n=5119; 2829 women)

and Offspring (n=4957, 2565 women) cohorts, who were 45 years and stroke-

free, to first incident stroke. They observed that women were significantly

(P<0.001) older (75.1 years versus 71.1 years for men) at their first-ever stroke,

had a higher stroke incidence above 85 years of age, lower at all other ages,

and a higher lifetime risk of stroke at all ages. There was no significant

difference in stroke subtype, stroke severity, and case fatality rates between

genders. Women were significantly (P<0.01) more disabled before stroke and in

the acute phase of stroke in dressing (59% versus 37%), grooming (57% versus

34%), and transfer from bed to chair (59% versus 35%). At 3 to 6 months post

stroke women were more disabled, more likely to be single, and 3.5 times more

likely to be institutionalized (P<0.01).

95
Klaus Kaae Andersen et al started a registry in 2001, with the aim of

registering all hospitalized stroke patients in Denmark, now holds information

for 39 484 patients. The patients underwent an evaluation including stroke

severity (Scandinavian Stroke Scale), CT, and cardiovascular risk factors. They

were followed-up from admission until death or censoring in 2007. Independent

predictors of death were identified by means of a survival model based on 25

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123 individuals with a complete data set. Of the patients 3993 (10.1%) had

haemorrhagic stroke. Stroke severity was almost linearly related to the

probability of having haemorrhagic stroke (2% in patients with the mildest stroke

and 30% in those with the most severe strokes). Factors favoring ischemic

strokes versus haemorrhagic stroke were diabetes, atrial fibrillation, previous

myocardial infarction, previous stroke, and intermittent arterial claudication.

Smoking and alcohol consumption favored haemorrhagic stroke, whereas age,

sex, and hypertension did not herald stroke type. Compared with ischemic

strokes, haemorrhagic stroke was associated with an overall higher mortality

risk (HR, 1.564; 95% CI, 1.441–1.696). The increased risk was, however, time-

dependent; initially, risk was 4-fold, after 1 week it was 2.5-fold, and after 3

weeks it was 1.5-fold. After 3 months stroke type did not correlate to mortality.
96
Fo¨rster et al performed a study in which from July 2004 until June

2007, 237 acute ischemic stroke (AIS) patients were treated with recombinant

tissue plasminogen activator (rtPA) within 3 hours after onset of symptoms in

our stroke unit. Baseline characteristics, etiology, CT/MRI stroke patterns,

clinical outcome, and complications of women were compared to those of men.

Of 237 acute ischemic stroke patients (mean age 70.7 years), 111 (46.8%)

were women and 126 (53.2%) were men. Women were older (P<0.001), but

history of hyperlipidemia (P=0.03), smoking (P=0.03), and coronary heart

disease (P<0.001) was less frequent than in men. Internal carotid artery

disease occurred more often in men (P=0.02), whereas atrial fibrillation was

observed more often in women (P=0.002). In men border zone/small embolic

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and lacunar stroke was found more frequently (39.7 versus 27.2%), whereas

women showed a higher percentage of large territorial stroke (72.8 versus

60.3%, P0.09). Baseline National Institute of Health Stroke Scale scores

(NIHSS score) (12.5 versus 11.3), NIHSS score at discharge (11.0 versus 9.5),

3-month-outcome modified Rankin Scale score, thrombolysis-related (17.1%

versus 13.5%) or independent complications (32.4% versus 30.2%), and

mortality after 3 months (13.5% versus 9.5%) were similar.

97
Gall et al collected data from May 1, 1996, to April 30, 1999, in the

North East Melbourne Stroke Incidence Study. Stroke symptoms, prestroke

medical history, in-hospital investigations, admission and discharge

medications, initial stroke severity, and 28-day mortality were recorded.

Multivariable regression was used to estimate sex differences in treatment,

investigations, and 28-day mortality. A total of 1,316 patients were included.

Women were older (mean age 76 +/- 0.6 versus 72 +/- 0.6, p < 0.01), had more

severe strokes (median NIH Stroke Scale score 6 versus 5, p < 0.01), and more

likely to experience loss of consciousness (31% versus 23%, p = 0.003) and

incontinence (22% versus 11%, p = 0.01) than men. Women were less often on

lipid-lowering therapy on admission. Echocardiography and carotid

investigations were less frequently performed in women due to greater age and

stroke severity. Women had greater 28-day mortality (32% versus 21%, p <

0.001) and stroke severity (44% versus 36%, p = 0.01) than men, but

adjustment for age, comorbidities, and stroke severity (for mortality only)

completely attenuated these associations.

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INTERSTROKE study, 1 a case control study conducted in 22 countries

worldwide between March 1, 2007 and April 23, 2010. In the first 3000 cases

(n=2337, 78%, with ischaemic stroke; n=663, 22%, with intracerebral

haemorrhagic stroke) and 3000 controls, significant risk factors for all stroke

were: history of hypertension (OR 2·64, 99% CI 2·26–3·08; PAR 34·6%, 99%

CI 30·4–39·1); current smoking (2·09, 1·75–2·51; 18·9%, 15·3–23·1); waist-to-

hip ratio (1·65, 1·36–1·99 for highest versus lowest tertile; 26·5%, 18·8–36·0);

diet risk score (1·35, 1·11–1·64 for highest versus lowest tertile; 18·8%, 11·2–

29·7); regular physical activity (0·69, 0·53–0·90; 28·5%, 14·5–48·5); diabetes

mellitus (1·36, 1·10–1·68; 5·0%, 2·6–9·5); alcohol intake (1·51, 1·18–1·92 for

more than 30 drinks per month or binge drinking; 3·8%, 0·9–14·4); psychosocial

stress (1·30, 1·06–1·60; 4·6%, 2·1–9·6) and depression (1·35, 1·10–1·66;

5·2%, 2·7–9·8); cardiac causes (2·38, 1·77–3·20; 6·7%, 4·8–9·1); and ratio of

apolipoproteins B to A1 (1·89, 1·49–2·40 for highest versus lowest tertile;

24·9%, 15·7–37·1). Collectively, these risk factors accounted for 88·1% (99%

CI 82·3–92·2) of the Population-attributable risk for all stroke. When an

alternate definition of hypertension was used (history of hypertension or blood

pressure >160/90 mm Hg), the combined Population-attributable risk was

90·3% (85·3–93·7) for all stroke. These risk factors were all significant for

ischaemic stroke, whereas hypertension, smoking, waist-to-hip ratio, diet, and

alcohol intake were significant risk factors for intracerebral haemorrhagic stroke.
98
Watila et al conducted a prospective study at the University Of

Maiduguri Teaching Hospital (UMTH) from 2005 to 2009. All patients admitted

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through the accident and emergency unit or directly to neurology unit with

clinically and radiologically proven stroke were enrolled into the study after

informed written or oral consent. History with emphasis on clinical presentation

and neurological examination were conducted by the authors. The National

Institutes Of Health Stroke Scale (NIHSS) was administered to all enrollees.

Ninety-one patients were enrolled for the study, 61 males (63%) and 30 females

(37%). There was no significant difference in the mean age (p=0.823). Females

were less likely to be formally educated (p=0.024). Females were more likely to

be in coma at time of presentation (p=0.003), but there was no significant

difference in weakness, facial paralysis, speech or swallowing difficulties,

hemianopia, headache and vomiting. Lacunar strokes were more frequent in

males (p=0.048). Females were less likely to smoke (p=0.046) or take alcohol

(p=0.027). We found 6.67% of the females with eclampsia as the possible

cause of stroke. Females had a higher NIHSS on discharge (p=0.047). This

finding support gender-related difference in stroke.

59