1. Pathogenesis and risk factors of cerebrovascular accidents (I)
Dr. Mamlook Elmagraby

2. Objectives of the lecture:
Upon completion of this lecture, students should be able to:
Build a list of the different causes that can lead to cerebrovascular accident
Explain the concepts of brain “Hypoxia”, “Ischemia” and “Infarction”
Understand the pathogenesis of thrombotic and embolic stroke and be able to identify clinical risk factors

3. Overview Cerebrovascular diseases include three major categories:
Thrombosis
Embolism
Hemorrhage
“Stroke” is the clinical term that applies to all these conditions
“Stroke” is acute neurologic dysfunction of vascular origin with sudden or rapid occurence of manifestations corresponding to the involvement of focal areas in the brain
Cerebrovascular disease can be considered as two processes :
Hypoxia, ischemia, and infarction
Hemorrhage resulting from rupture of CNS vessels

4. Classification of Stroke
The most common cerebrovascular disorders are:
Global ischemia
Embolism
Hypertensive intraparenchymal hemorrhage
Ruptured aneurysm

6. Hypoxia, Ischemia, and Infarction
The brain may be deprived of oxygen by several mechanisms:
Hypoxia caused by a low partial pressure of oxygen
Impairment of the blood's oxygen-carrying capacity
Inhibition of oxygen use in the tissue
Ischemia (transient or permanent)
Two principal types of acute ischemic injury are recognized:
Global cerebral ischemia
Focal cerebral ischemia
Hypoxia diminished availability of oxygen to the body tissues

7. Hypoxia, Ischemia, and Infarction
When blood flow to a portion of the brain is reduced, the survival of the tissue at risk depends on:
The presence of collateral circulation
The duration of ischemia
The rapidity of the reduction of blood flow
Special response to ischemia in the CNS:
Inappropriate release of excitatory neurotransmitters such as glutamate → initiating cell damage
Collateral circulation is the alternate circulation around a blocked artery or vein  via another path, such as nearby minor vessels. 
It may occur via preexisting vascular redundancy, as in the circle of Willis in the brain, or
it may occur via new branches formed between adjacent blood vessels (neovascularization), as in the eye after aretinal  embolism

8. Global Cerebral Ischemia
Widespread ischemic-hypoxic injury can occur in the setting of severe hypotension, when systolic pressures fall below 50 mm Hg
Neurons are the most sensitive among CNS cells
There is variability in the susceptibility of populations of neurons in different regions of the CNS
In mild cases: there may be only a transient post-ischemic confusional state followed by complete recovery
With severe global cerebral ischemia, extensive neuronal death occurs
Brain death is the complete loss of brain function (including involuntary activity necessary to sustain life)
It differs from persistent vegetative state, in which the person is alive and some autonomic functions remain
It is also distinct from an ordinary coma as long as some brain and bodily activity and function remains

9. Global Cerebral Ischemia
Generalized reduction of available oxygen that affects the whole CNS may cause:
Transient ischemic attacks (TIAs): These lack morphologic sequelae
Selective neuronal damage: Typically it first affects the most vulnerable neurons (hippocampus)
Border zone infarcts:
Laminar necrosis: Global ischaemia of cerebral cortex results in uneven damage because of different cerebral vasculature
Superficial areas of cortical layers escape damage while deeper layers are necrosed

10. Global Cerebral Ischemia
Border zone infarcts
Circulatory flow in the brain by anterior, middle and posterior cerebral arteries has overlapping circulations
In ischaemia, perfusion of overlapping zones, being farthest from the blood supply, suffers maximum damage
In ischaemia, There may be necrosis of these overlapping zones called watershed or border zone infarcts
Particularly vulnerable is the border zone of the cerebral cortex between the anterior and middle cerebral arteries territories

11. Brain, borderzone infarct – Gross, coronal section
The hemorrhagic lesion in the right cerebral hemisphere in this case lies at the boundary between the anterior and middle cerebral artery territories.

12. Global Cerebral Ischemia
Morphology
The brain is swollen, the gyri are widened, and the sulci are narrowed
The cut surface shows poor demarcation between gray and white matter

13. Brain, global hypoxic-ischemic encephalopathy – Gross, coronal section
This is the brain from a patient who died approximately 5 days after a cardiac arrest.
The patient was vigorously resuscitated en route to the hospital.
Although a sinus rhythm was established, the patient remained comatose and ventilator-dependent throughout his hospital stay.
Note the generalized swelling and irregular discoloration of gray matter, features indicative of irreversible, widespread brain injury caused by total circulatory arrest.

14. Global Cerebral Ischemia
The microscopic changes are grouped into three categories:
Early changes
Occurring 12 to 24 hours after the insult
microvacuolization, eosinophilia of the neuronal cytoplasm
Later nuclear pyknosis and karyorrhexis
Similar changes occur later in astrocytes and oligodendroglia
Neutrophils infiltration
Hippocampus, Cerebellum, and Cortical pyramidal neurons are the most susceptible to global ischemia

15. Global Cerebral Ischemia
Subacute changes
occurring at 24 hours to 2 weeks
necrosis of tissue, influx of macrophages, vascular proliferation, and reactive gliosis
Repair
after 2 weeks
removal of all necrotic tissue, loss of normally organized CNS structure, and gliosis

16. Focal Cerebral Ischemia
Cerebral arterial occlusion → focal ischemia and infarction of a specific area
The location and the extent of tissue damage are determined mainly by adequacy of collateral flow
The major source of collateral flow is the circle of Willis
Partial reinforcement is available over the surface of the brain
Collateral circulation is the alternate circulation around a blocked artery or vein  via another path, such as nearby minor vessels. 
It may occur via preexisting vascular redundancy, as in the circle of Willis in the brain, or
it may occur via new branches formed between adjacent blood vessels (neovascularization), as in the eye after aretinal  embolism
Circle of Willis provides a complete collateral flow for internal carotid and vertebral arteries
Small terminal cerebral arteries, on the contrary, are end-arteries and have no anastomosis. Hence, occlusion of these branches will lead to an infarct
Anastomosis a connection between adjacent channels of a network

17. Focal Cerebral Ischemia
There is little if any collateral flow for the deep penetrating vessels
Occlusive vascular disease may be due to:
In situ thrombosis
Embolization from a distant source
Vasculitis 

18. In situ thrombosis
The majority of thrombotic occlusions are due to atherosclerosis
The most common sites of primary thrombosis causing cerebral infarction are:
The carotid bifurcation
The origin of the middle cerebral artery
ends of the basilar artery
The evolution of arterial thrombosis:
progressive narrowing of the lumen
Anterograde extension
Fragmentation and distal embolization

19. Embolism Embolism to the brain occurs from a wide range of origins:
Cardiac thrombi
Thromboemboli arising within the carotid arteries
The territory of distribution of the middle cerebral artery is most frequently affected by embolic infarction
Emboli tend to lodge where blood vessels branch or in areas of preexisting luminal stenosis

20. Infarction
Cerebral infarction is a localised area of tissue necrosis caused by local vascular occlusion
Infarcts are subdivided into two groups :
Hemorrhagic (red) infarction (emboli)
Nonhemorrhagic infarcts (thrombosis)
The clinical management of patients with these two types of infarcts differs

21. Infarction Morphology The appearance of a nonhemorrhagic infarct:
During the first 6 hours, little can be observed
By 48 hours
The tissue becomes pale, soft, and swollen
From 2 to 10 days
The brain becomes gelatinous and friable
Boundary between normal and abnormal tissue becomes clear
From 10 days to 3 weeks, the tissue liquefies, leaving a fluid-filled cavity lined by dark gray tissue

22. Brain, acute infarct, middle cerebral artery territory – Gross, coronal section
the necrotic tissue is swollen
Brain, pons, infarct – Gross, horizontal section
The necrotic area in this case is in the pons, and has started to fall away from the adjacent viable parenchyma. An occlusive thrombus is still present in the lumen of the basilar artery

23. Brain, organizing infarct – Gross, coronal section
This image demonstrates an organizing infarct, also in the distribution of the left middle cerebral artery. The organizing infarct is a relatively well-demarcated, yellow area in the lateral cerebral cortex
Brain, left frontal infarct – Gross, whole brain
This is a left lateral view of the patient's brain prior to sectioning, demonstrating a cystic lesion involving the lateral left frontal lobe

24. Infarction On microscopic examination: After the first 12 hours
Ischemic neuronal change (red neurons)
Edema predominate
Endothelial and glial cells swell
Myelinated fibers begin to disintegrate
Up to 48 hours, neutrophilic emigration progressively increases and then falls off
After the first 2-3 days, there is progressive invasion by macrophages and there is astrocytic and vascular proliferation

25. Brain, organizing infarct
The presence of lipid-laden macrophages, characterized by foamy cytoplasm, distinguishes organizing infarcts from acute infarcts.

26. Infarction
In the following weeks to months, the macrophages clear away the necrotic debris by phagocytosis followed by reactive astrocytosis, often with little fine fibrosis
After 3-4 months an old cystic infarct is formed which shows
a cyst with peripheral gliosis
The microscopic picture and evolution of hemorrhagic infarction is similar to ischemic infarction, with the addition of blood extravasation and resorption
Astrocytosis An increase in the number of astrocytes

27. Brain, acute cerebral hemorrhagic infarct – Gross, coronal section
The necrotic zone in this example is marked by extensive hemorrhage in the medial aspect of the right cerebral hemisphere

28. Clinical Features of ischemic stroke
Clinical features of ischemic stroke greatly depend on the size and location of the infarcts
Large hemispheric and brainstem infarcts present with loss of consciousness
During the acute stage, ischemic edema when severe, aggravates the clinical course and may cause danger to the patient’s life
There can be improvement in severity of symptoms associated with:
Reversal of injury in the ischemic surrounding area
Resolution of associated local edema

29. Clinical Features of ischemic stroke
Seizures may occur during the acute stage or several weeks or months later Mortality rate ranges from 10% to 20% during the first month Neurologic deficits remain in about 50% of survivors Behavioral changes, depression, and cognitive abnormality add to the clinical picture Multiple cortical or subcortical infarcts can leads to multiinfarct dementia
Behavioral changes  forgetful, careless, irritable or confused. Stroke survivors may also feel anxiety, anger or depression.

30. Transient ischemic attack (TIA)
A mild and short ischemic attack without infarction produces transient impairment of neuronal function
Focal neurologic symptoms and signs develop suddenly, progress rapidly, and usually resolve within less than 24 hours