Lecture Outline:

• Introduction
• Cellular Pathology of the CNS
• Cerebral Edema, Raised ICP, Herniation, & Hydrocephalus
• Malformations & Developmental Diseases
• Perinatal Brain Injury
• Trauma
• Cerebrovascular Diseases
• Infections
• Transmissible Spongiform Encephalopathy (Prion Diseases)
• Demyelinating Diseases
• Degenerative Diseases
• Genetic Metabolic Diseases
• Toxic & Acquired Metabolic Diseases
• Tumors

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III. Perinatal Brain Injury
• A variety of exogenous forces may injure the developing
brain
• Injuries that occur early in gestation may be difficult to
distinguish from malformation (why?)
• Injuries that occur in the perinatal period are an important
cause of childhood neurologic disability
• Include:
Cerebral Palsy
Intraparenchymal Hemorrhages

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Cerebral Palsy:
• A syndrome referring to a non-progressive neurologic motor
deficit characterized by spasticity, dystonia, ataxia/athetosis,
and paresis attributable to insults during the prenatal and
perinatal periods.
• Signs and symptoms may not be apparent at birth
• Post-mortem examination reveal wide range of
neuropathological findings

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V. Cerebrovascular Diseases
Hypoxia, Ischemia, & Infarction
Intracranial Hemorrhages
 Intracerebral Hemorrhages
 Subarachnoid Hemorrhages & Ruptures Saccular
Aneurysms
 Vascular Malformations
Hypertensive Cerebrovascular Diseases
 Lacunar Infarcts
 Slit Hemorrhages
 Hypertensive Encephalopathy

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Cerebrovascular Disease (CVD)
• Third leading cause of death and most prevalent neurologic
disorder in terms of both morbidity and mortality
• Term denotes any abnormality of brain caused by a
pathologic process of blood vessels
• Includes three major categories:
i. Thrombosis
ii. Hemorrhage, &
iii. Embolism
• ‘Stroke’ is a clinical term that apply to all 3, especially used
when symptoms begin acutely

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Pathophysiology & Pathologic
Anatomy of CVD:
• Two processes:
i. Hypoxia, ischemia, and infarction
resulting from impairment of blood
supply and oxygenation
ii. Hemorrhage resulting from rupture of
blood vessels

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Hypoxia, Ischemia, & Infarction
• Brain as vital organ (?)
• Brain weight vs its blood supply (?)
• Brain weight vs its oxygen consumption (?)
• Normal cerebral blood flow (?)
• Limiting substrate in brain metabolism (?)
• Causes of brain hypoxia (?)
• Hypoxia risk modifying factors (?)

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Two principal types of acute
ischemic injury:
1. Global cerebral ischemia (ischemic / hypoxic
encephalopathy) occurs when there is generalized
reduction of cerebral perfusion, such as in cardiac arrest,
shock, and severe hypertension.
2. Focal cerebral ischemia follows reduction or cessation of
blood flow to a localized area of the brain due to large-
vessel disease ( such as embolic or thrombotic arterial
occlusion in a setting of atherosclerosis) or to small-vessel
disease ( such as vasculitis or occlusion secondary to
arteriosclerotic lesions)

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 Global Cerebral Ischemia
(Hypotension, Hypoperfusion & Low
Flow State):
• Autoregulatory mechanisms are inadequate to compensate for the
reduction in blood flow below a systolic pressure of approximately 50
mm Hg …resulting in brain parenchymal injury
• Certain regions and cell populations are more susceptible than others to
hypoxic-ischemic injury (?)
• Among the neurons, certain subpopulations, including some of the
pyramidal cells in the hippocampus, the Purkinje cells of the cerebellum
are particularly sensitive
• Areas of the brain located at the junctions of arterial territories (i.e.,
arterial border zones, sometimes termed "watershed" areas) are also
particularly susceptible

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C/F:
• A number of factors may modify the degree of parenchymal
injury, including:
Age of the patient
Duration of the circulatory disturbance, and
Temperature (hypothermia increases the resistance of
the brain to hypoxic-ischemic injury whereas
hyperthermia worsens the effects of hypoxic-ischemic
injury)
• The resulting deficits range from transient neurologic
disturbances, severely impaired neurologically & deeply
comatose (persistent vegetative state) to "brain death“

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Focal Cerebral Ischemia (Ischemic
Stroke)
• Reduction or cessation of blood flow to a
localized area of the brain due to a large
vessel disease
• The underlying processes is due to either of
the following:
Emboli
Thrombosis or
Vasculitis

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Thrombotic Occlusions:
• The majority are due to atherosclerosis
• The most common sites are
Carotid bifurcation
Origin of the middle cerebral artery &
Either end of basilar artery

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Embolism:
• Occurs from wide range origins:
Cardiac mural thrombi are among the most common
sources
Myocardial infarct, valvular disease & atrial
fibrillation are important predisposing factors
Other sources are emboli from atheromatous
plaques within the carotid arteries
• Emboli tend to lodge where blood vessels branch or areas of
preexisting luminal stenosis
• The distribution of middle cerebral artery (the direct
extension of the internal carotid artery) is most frequently
affected by embolic infarction
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• Infarcts are subdivided into two broad groups
based on macroscopic appearance:
I. Hemorrhagic (red) infarction: characterized
macroscopically by multiple petechial
hemorrhages; typically associated with embolic
events. The hemorrhage is presumed to be
secondary to reperfusion of damaged vessels &
tissue either through collaterals or after lysis of
the occlusive material
II. Non-hemorrhagic (pale/bland/anemic)
infarcts: Usually associated with thrombosis
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Morphology:
• The macroscopic appearance of nonhemorrhagic
infarct changes with time:
By 48 hrs.: the brain becomes pale, soft & swollen
From 2 to 10 days: the brain becomes gelatinous &
friable
From 10 days to 3 weeks: the tissue liquefies ,
eventually leaving fluid filled cavity

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• On microscopic examination:
After the first 12 hrs: Ischemic neuronal change (red
neurons) & edema predominates.
Up to 48hrs: Neutrophils migration increases, &
After 48hrs: Phagocytic cells dominate in the next 2 to 3
wks

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• Microscopic picture of hemorrhagic infarction
parallels ischemic infarction with addition of blood
extravasation & resorption.

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C/F:
• The area of brain that is affected determines
whether the patient becomes asymptomatic or
develops a hemiplegia , sensory deficit, aphasia or
other deficit.

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Hemorrhage Resulting from
Rupture of Vessels
• May occur at any site within the CNS
• Hemorrhages within the brain parenchyma &
subarachnoid space are often manifestation of
underlying cerebrovascular disease where as
hemorrhages within epidural & subdural space are
typically related to trauma

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Intracerbral (Intraparenchymal)
Hemorrhage
• Spontaneous (non traumatic) intraparenchymal
hemorrhages occur most commonly in middle to late adult
life with peak incidence at age of 60yrs
• Most are caused by rupture of a small intraparenchymal
vessel
• Hypertension (HTN) is the most common underlying cause
of primary brain parenchymal hemorrhage (50%)
• HTN causes a number of abnormalities in vessel wall
including accelerated atherosclerosis in large arteries,
hyaline arteriolosclerosis in small vessels
• Arteries with this changes are presumably weaker than are
normal vessels & are therefore more vulnerable to rupture

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Morphology:
• Hypertensive intraparenchymal hemorrhage may originate:
Putamen (50-60% - the most common site)
Thalamus
Pons, or
Cerebellar hemispheres
• The hemorrhages are characterized by extravasation of
blood with compression of the adjacent parenchyma
• Old hemorrhages show an area of cavitary destruction of
brain with a rim of brownish discoloration

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C/F:
• Intracerebral hemorrhage can be:
 Clinically devastating - when it affects large portions of
the brain & extends into the ventricular system or
 Clinically silent – if it affects small regions
 Over weeks or months , there is gradual resolution of
the hematoma with clinical improvement.
• The location of the bleed will determine the clinical
manifestation

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Subarachnoid Hemorrhage
• The most frequent cause is a rupture of a saccular
(berry) aneurysm
Berry aneurysm (saccular or congenital
aneurysm):
• It is the most common type intracranial
aneurysm
• Most occur in anterior circulation of circle of
Willis

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Pathogenesis:
• Although majority occur sporadically, genetic
factors may play a role
• There is increased risk of occurrence among
patients with certain heritable conditions (
autosomal dominant polycystic kidney disease)
• Cigarette smoking & hypertension are predisposing
factors
• The aneurysms are not present at birth but develop
over time owing to underlying defect in the media
of the vessel
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Morphology:
• Un-ruptured berry aneurysm is a thin walled out
pouching at arterial branch point along the circle of
Willis
• It measures a few mms to 2 to 3 cm in diameter

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C/F:
• Rupture of an aneurysm is most frequent in the fifth
decade
• The probability of rupture increases with the size of the
lesion
• In most cases, rupture is associated with acute
increases in intracranial pressure such as straining at
stool
• Blood under arterial pressure is forced into sub-
arachinoid space & patients are stricken with sudden
excruciating headache typically ‘worst headache I’ve
ever had’ & rapidly lose consciousness.
• CSF: Xanthochromasia

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