RISK FACTORS &

PATHOPHYSIOLOGY OF STROKE
 Definition

 Definition of ischemic stroke: An episode of

neurological dysfunction caused by focal
cerebral, spinal, or retinal infarction
 Definition of stroke caused by
intracerebral hemorrhage: Rapidly
developing clinical signs of neurological
dysfunction attributable to a focal collection of
blood within the brain parenchyma or
ventricular system that is not caused by
trauma.
 Definition of stroke caused by
subarachnoid hemorrhage: Rapidly
developing signs of neurological dysfunction
and/or headache because of bleeding into the
subarachnoid space (the space between the
arachnoid membrane and the pia mater of the
brain or spinal cord), which is not caused by
trauma.
 Stroke accounts for 10% of all-cause
mortality

Tuberculosis Malaria
Diarrhoea
Perinatal causes
2% Other causes
3% 3%
Chronic obstructive pulmonary 4%
disease 5% 27%

HIV/AIDS 5%

Respiratory infections 7%
Coronary heart
disease
9%
13%
Accidents Stroke Cancer

10% 12%

Since 80s, a significant increase (> 2-fold ) has been noticed in incidence of stoke :
1–2 /1.000 people in USA, 2–2.5/1.000 in Western και 3–3.5/1.000 in Eastern Europe

American Stroke Association. Heart Disease and Stroke Statistics 2004

STROKE: A Major Problem for Public Health
increased ~65% until 2025

Estimated number of strokes in USA during 2002-2025

Broderick JP et al. Stroke 2004;35:205-211

 Epidemiological data with clinical significance

 Stroke is strongly correlated with age and CVRF existence

 10% of strokes are fatal
 ~55% patients will experience a new & often more severe
stroke or die within the next 5 years
 ~30% of survivors becomes disabled and/or develops vascular
dementia

«cross» cardiovascular risk!

 After a stroke: x2 - 3 risk for myocardial infarction
 In ~10% of patients with myocardial infarction, stroke will
occur within the next 5 years

Framingham Heart Study; American Heart Association, Heart and Stroke Facts statistical update, Lees KR, et al. BMJ 2000;320:991–994; Hankey GJ, Warlow
CP. Lancet 1999;354:1457–1463
 Non- modifiable Risk Factors

14
Frequency of Stroke 12
 Men 12,0
11,5

 Women
related to age &

% of population
10
8 6,6 6,3
gender 6
4 3,1 3,0
2,1
1,1 0,8 1,2
2
0,4 0,3
0
20-34 35-44 45-54 55-64 65-74 75+
Age

 Race: (e.g Afro-Americans increased risk)

 Family history of stroke (inheritance ?)
 History of stroke or myocardial infarction
(Early recurrence is observed after embolic stroke:
cardioembolism & stroke from extracranial
atherosclerosis)
NHANES: 1999-2002 CDC/NCHS and NHLBI
 Modifiable risk factors
Major Other
 Obesity
 Insulin resistance
 Hypertension  Decreased physical activity
 Increased alcohol
 Diabetes consumption
 Heart disease (CHD, CHF)
 Dyslipidaemia  Vasculitis
(infectious or collagen
diseases)
 Smoking  Migraine
 Hypothyroidism
 Risk for embolic events  Sleep apnoea syndrome
in heart or carotid disease  Hematological disorders
(Hypercoagulation or emboli)
 Predisposition for thrombotic
events
(Hyperhomocysteinemia,
female hormones)
 10yr risk for Stroke in Adults 55 yrs old
according to basic Risk Factors
(Framingham Heart Study)

30 27
Estimated 10-Year Rate (%)

25 22.4
19.1
20
14.8
15

10 8.4
5.4 6.3
5 4 3.5
2.6 2
1.1
0

A B C D E F
Men Women

A B C D E F
Systolic BP 95-105 130-148 130-148 130-148 130-148 130-148 mmHg
Diabetes no no yes yes yes yes
Smoking no no yes yes yes yes
Previous AF no no no no yes yes
Previous CVD no no no no no yes
Stroke 1991;22:312-318
 Atherosclerosis
From risk factors to endothelial injury & CVD

LDL-C BP Risk factors Diabetes Smoking Cardiac failure

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

Endothelium Collagen growth Proteinolysis

PAI-1 VCAM,ICAM,
factors
cytokines

Vascular injury &

Thrombosis Inflammation Vasocontraction Plaque rupture
remodeling

Adhesion molecules
CV Clinical events
VCAM: vascular cell adhesion molecule,
ICAM: intercellular adhesion molecule
PAI-1: plasminogen activator inhibitor 1
Gibbons GH. N Engl J Med 1994
Normal Arterial Wall
(intima, Media, Adventitia)

Intima:
Endothelium
Internal elastic laminae

Media:
Smooth muscle cell
Lumen
Collagen proteins

External elastic laminae

Endothelial dysfunction in atherosclerosis
(Early changes)

up-regulation of endothelial adhesion

molecules

Leucocyte migration into the

arterial wall

Penetration of lipoproteins

greater permeability of the

endothelium

Leucocyte adhesion
Lipid core formation (fatty streak)
in atherosclerosis

Platelets’ adhesion and

coagulation

Migration of smooth
muscle cells

Foam cells formation

T cells activation

Adhesion and penetration

of leucocytes
 Formation of atherosclerotic plaque
(death & rupture of foam cells in fatty streak)

Formation of necrotic core

Accumulation of macrophages

Formation of fibrous cap

Rupture of plaque and thrombus formation
(supsequent luminal occlusion)

Intravascular thrombus

Lipid layer

Thrombus inside the plaque

 Progression of atherosclerosis
Threshold
Decades Years-Months Months-Days
Healthy Subclinical Symptomatic

Intima
Lumen
Media

Plaque

Threshold

Thrombus
Intima
Lumen
Media

Plaque

HEALTH POLICY PRIMARY PREVENTION SECONDARY PREVENTION

Diet and lifestyle changes Drug treatment Aggressive drug therapy
 Pathophysiology of Stroke

Brain injury
Due to:

 Vascular occlusion or hemodynamic disturbances from

intracranial or extracranial vascular injury (stenosis, splitting,
vasculitis)

 Interruption of cerebral blood flow

 Neuronic death (infarct) when self regulation of blood flow and

collateral circulation are insufficient

Results to:
 Functional body disorders which are controlled by the damaged
part of the brain
 Thromboembolic
Brain
ISCHEMIC infarct

HEMORRHAGIC

Brain vessel
thrombosis

Willis
cycle Emboli from
extracranial
thrombosis
Arterio-venous
Dysplasia TIA

Intracerebral
hemorrhage
 Incidence – Mortality of
ischemic & hemorrhagic Stroke
The majority of strokes are ischemic

•Thrombotic Ischemic strokes Hemorrhagic strokes

•TIA • Intracranial
•Subcortical- • Subarachnoidal
lacunar
•Cardio or

Mortality 1st month %

arterio-arterial
embolic
 Types-Pathogenesis of Stroke
 Thrombotic : occlusion or stenosis of the vessel with hemodynamic effects (>
70%) due to growth or rupture of atherosclerotic plaque & consequent
thrombosis

 Embolic : emboli originate from heart, aortic arch & major cervical vessels

 Small subcortical or lacunar infarcts : due to lipohyalinosis of small brain

vessels (< 15mm diameter) in thalamus, pons, basal gaglia, in elderly patients
with hypertension or diabetes

 Transient Ischemic Attacks (ΤΙΑ): «small» strokes due to temporarily

reduced blood supply, secondary to small platelet emboli, which rapidly
dissociate. Symptoms disappear within a few minutes to 24h. Appearance and
incidence of TIA is a significant predictive factor for the vascular system’s state
and the occurrence of a permanent stroke

• PRIND (PRolonged Ischemic Neurological Deficiency): is characterized by

restoration of clinical symptoms within the first 3 weeks
 Types-Pathogenesis of Stroke

• Hemorrhagic Stroke: caused by thinning, aneurysmatic dilatation of

vascular wall, rupture of small vessels, microaneurysms or
arteriovenous dysplasia. It is often accompanied by rapid deterioration,
increased endocranial pressure, mass effect, hydrocephalus. However,
in those who manage to survive, less severe disability compared to
ischemic strokes of equivalent extent occurs.
• Pervasive - global cerebral ischemia: represents cardiovascular
dysfunction like cardiac arrest or severe hypotension and pervasive
vascular lesions like chronic cerebral microangiopathy. It is usually due
to hypertension and if it lasts only few minutes, the result is transient
global amnesia. In case of longer duration, coma, vegetative state
without voluntary mobility due to cortical injury or brain death with
isoelectric line in the EEG but preservation of cardiac function, ensues.
 Pathophysiology of ischemic infarct -
Penumbra
• The occlusion of a cerebral vessel is Infarct Penumbra
followed by formation of a central
irreversible tissue necrotic lesion,
where the brain blood flow is
reduced < 15% (<20 ml/100gr/min),
with a peripheral zone, the Penumbra
(20 - 30 ml/100gr/min), where tissue
is viable and functional disturbance is
reversible due to partial preservation
of blood supply via emissary vessels,
if ischemia reverses on time
• Depending on the grade of blood
flow reduction and its duration, after
an ischemic interval, Penumbra
becomes necrotic
• Experimental studies report that the
infarct ιs formed 3-12 h after
initiation of ischemia and continues to
develop even after 24h, although in a
much slower rate (24-72h <30%
increase)
 Pathophysiology of ischemic stroke
Neuronal disturbances
 Decreased energy supply to the cerebral
parenchyma with simultaneous decrease
in Ο2, Glucose and ATP production (25%
of normal levels in the central area, 50-
70% in Penumbra)
 Anaerobic glycolysis and metabolic
acidosis
 Release of excitative aminoacids
(glutamino-acid) and inflammatory
mediators in extracellular space,
decreased energy production, ions and
water intracellular entrance, increase of
catabolic enzymes and free radicals,
 neuron cells oedema, cellular membrane
injury and cytolysis
 Disturbance of regional blood flow
autoregulation (regional vasodilation)
and as a consequence it’s absolute
dependency from systemic BP (thus
when BP reduces, ischemia worsens)
 Angiogenic oedema around the ischemic
area because of blood-brain barrier
destruction (endothelial cell connections,
1-4 days after ischemia), may cause
compressive effect and necrotic area
expansion
 Pathophysiology of ischemic stroke
• Large hemispheric strokes (10-20% in the total of ischemic strokes) are
due to middle cerebral artery occlusion

• Several mechanisms contribute to ischemic stroke evolution, the main

being the clot expansion

•Other possible mechanisms during the first 48-72 h after ischemic stroke
initiation are:
- cerebral oedema development and space occupational action,
- metabolic disturbances like hyperglycemia, hyponatremia,
- hemorrhagic transformation,
- fever (infection) aggravating ischemic neuron metabolism
 Ischemic infarct: Frequently, up to 50%, there is
delay in CT imaging within 48 h

“Normal CT” at admission of an Large infarct in the area of middle brain artery
ischemic stroke with left hemiparesis| causing compressive effect, 48h after admission
 Hemorrhagic Stroke

Admission CT of hemorrhagic stroke with Subdense appearance and severe compressive effect of
left hemiparesis and persistent headacne extented oedema around hematoma, 48h after admission
Thank you for your attention!
 Pertanyaan

1. Jelaskan ischemic penumbra

2. Jelaskan stroke iskemik menurut Sacco, et al
2013!
3. Jelaskan Plasminogen activator
4. Jelaskan thrombosis
5. Jelaskan emboli
6. Jelaskan hubungan antara systemic
hypotension dan stroke
7. Sebutkan marker stroke