10: Cerebrovascular Disease

Question 1

What precipitates focal cerebral ischaemia

Answer 1

• Lack of blood supply leads to reduced O2 delivery
  
  • Oligemia
  • Penumbra
  • Infarct core
  • Penumbra concept
    ○ Area of infarct that is recoverable if blood supply returned

Question 2

Factors influencing extent of cerebral ischaemia

Answer 2

○ Duration of ischaemia
○ Magnitude + rapidity of the reduction flow
○ Adequacy of collateral flow

Question 3

Discuss the different causes of occlusive vascular disease.

Answer 3

- Embolisation
		○ Carotid artery atherosclerosis
		○ Left atrial mural thrombus - AF
		○ Left ventricular mural thrombus - MI
		○ Paradoxical thromboemboli
		○ Endocarditis
		○ Aortic atherosclerosis
		○ Mural thrombus - aortic aneurysm
		○ Other - tumour, fat, air
	- Thrombosis
		○ Origin of middle cerebral artery
		○ Either end of basilar artery
		○ Carotid bifurcation
	- Vasculitis
		○ Infectious
			§ Opportunistic infections - aspergillosis
			§ Other infections - syphilis, tuberculosis
		○ Non-infectious
			§ Systemic - polyarteritis nodosa
			§ Non-systemic - primary angiitis
		○ Other
			§ Hypercoagulable states
			§ Drug abuse - amphetamines, heroin, cocaine
			§ Dissecting aneurysm

Question 4

How are cerebral infarcts subdivided?

Answer 4

• Non-haemorrhagic
  
  • Haemorrhagic
    ○ Start as non-haemorrhagic
    ○ Intravascular occlusive material dissolved or fragmented
    ○ Ischaemia-reperfusion injury damages small blood vessels
    ○ Secondary haemorrhagic transformation

Question 5

Ages of infarcts

Answer 5

• Acute < 1 day
  
  • Subacute = 1-2 days
  • Healed = 2 days +

Question 6

Morphological features of cerebral infarcts

Answer 6

- Macroscopic 
		○ < 6 hours = minimal change
		○ 6 hours - 2 days 
			§ Pale, soft, swollen tissue
			§ Reduced grey-white differentiation
		○ 2 days - 10 days
			§ Gelatinous + friable
			§ Distinct boundary between normal and infarcted tissue
		○ 10 days - 3 weeks
			§ Tissue liquefies
			§ Fluid-filled cavity expands to remove all dead tissue
	- Micro
		○ < 12 hours
			§ Minimal change
			§ Dead red neurons
			§ Perineuronal vacuolation
		○ 12 hours to 1 day
			§ Neutrophils infiltrate
		○ 1 - 2 days
			§ Macrophages infiltrate
			§ Reactive astrocytes organise over time
		○ 2 days +
			§ Astrocytic response recedes
			§ Dense meshwork of glial fibres + new capillaries left

Question 7

What are lunar infarcts

Answer 7

• Small (2-15mm) noncortical infarcts caused by occlusion of single penetrating branch of large cerebral artery

Question 8

Common locations of lunar infarcts

Answer 8

○ Putamen
		○ Globus pallidus
		○ Thalamus
		○ Internal capsule
		○ Deep white matter
		○ Caudate nucleus
		○ pons

Question 9

Causes of lacunar infarcts

Answer 9

• Hypertension
  
  • Arteriolosclerosis of deep penetrating arteries + arterioles
  • Thrombosis and complete vessel occlusion
  • Lacunar infarct

Question 10

Morphology of lunar infarcts

Answer 10

○ Infarcts < 15 mm in putamen and globus pallidus

Question 11

What causes intraparenchymal haemorrhages and how are they subcategorised?

Answer 11

• Rupture of small intraparenchymal vessel
  
  • Primary
    ○ Hypertension
    ○ Cerebral amyloid angiopathy
  • Secondary
    ○ AVM
    ○ Tumour
    ○ Thrombocytopenia
    ○ Sickle cell disease

Question 12

Where do hypertensive intraparenchymal haemorrhages typically arise

Answer 12

Occurs in putamen in 50-60% of cases

Question 13

How does hypertension affect intracerebral vessels

Answer 13

• Hypertension leads to vessel wall abnormalities
  ○ Accelerate atherosclerosis in larger arteries
  ○ Hyaline arteriolosclerosis in small arteries
  ○ Proliferative changes and frank necrosis of arterioles
  
  • Arteriolar walls affected by hyaline change
    ○ Thickened by more vulnerable to rupture
    ○ Most prominent in basal ganglia and subcortical white matter

Question 14

Which vessels and areas of the brain does cerebral amyloid angiopathy typically affect?

Answer 14

• Risk factor most commonly associated with lobar haemorrhages
  
  • Amyloidogenic peptides deposited in wall of medium and small-calibre meningeal, cortical and cerebellar vessels
    ○ Vessels rigid - fail to collapse during tissue processing and sectioning
  • Primarily seen in leptomeningeal and cortical vessels

Question 15

Histological features of intraparenchymal haemorrhage

Answer 15

○ Central core of clotted blood that compresses the adjacent parenchyma
○ -> secondary infarction of parenchyma
○ Anoxic neuronal and glial changes as well as oedema
○ Haemosiderin and lipid-laden macrophages appear
○ Proliferation of reactive astrocytes seen in peripherally of lesion
○ Old haemorrhages show wares of parenchymal cavity destruction with rim of brownish discolouration

Question 16

What are the causes of nontraumatic SAH?

Answer 16

• Saccular (berry) aneurysm
  
  • Rupture of primary intracerebral haemorrhage
  • Vascular malformations
  • Haematologic disturbances
  • Tumours

Question 17

Where do saccular aneurysms typically arise and what can cause their development?

Answer 17

• Most common type of intracranial aneurysm
  
  • Found in 2% of the population
  • Most often found in the anterior section
  • Near major arterial branch points

Question 18

What conditions are saccular aneurysms associated with

Answer 18

- Certain Mendelian disorders
		○ Autosomal dominant polycystic kidney disease
		○ Ehlers-Danlos syndrome (vascular subtype)
		○ Neurofibromatosis type 1
		○ Marfan syndrome
	- Fibromuscular dysplasia of extracranial arteries
	- Coarctation of the aorta
	- Modifiable factors
		○ Smoking
		○ Hypertension
		○ Atherosclerosis
		○ Cocaine use

Question 19

Morphology of saccular aneurysms

Answer 19

• Gross
  ○ Bright red shiny surface
  ○ Translucent wall
  
  • Micro
    ○ Arterial wall adjacent to neck of aneurysm shows intimal thinning and attenuation of media
    ○ Smooth muscle and intimal elastic lamina do not extend into neck and absent from aneurysm sac itself
    ○ Sac made of thickened hyalinised intima and covering of adventitia
    ○ Presence of thrombi in aneurysm

Question 20

Prognosis of saccular aneurysm

Answer 20

○ Rule of thirds
§ 1/3 = fatality with first rupture
§ 1/3 = survive with significant disability
§ 1/3 = recover without major disability

Question 21

High risk groups for saccular aneurysm rupture

Answer 21

○ 50-60 years
		○ Slightly more frequent in women
		○ Rupture at a rate of 1.3% per year
			§ Risk increases with aneurysm size
			§ Those greater than 10mm have 50% risk of rupture
		○ Rupture may occur at any time
			§ In 1/3 associated with acute increases in intracranial pressure
				□ Straining stool 
				□ Sexual orgasm
				□ Childbirth

Question 22

Complications of saccular aneurysm rupture

Answer 22

○ Acute
			§ Vasospasm
			§ Hydrocephalus
			§ Rebleeding
			§ Seizures
			§ Cardiac arrhythmias
		○ Chronic
			§ Epilepsy
			§ Cognitive dysfunction
			§ Emotional dysfunction
			§ Meningeal fibrosis
			§ Hydrocephalus

Question 23

Causes of vascular dementia

Answer 23

• Multiple, bilateral, grey matter (cortex, thalamus, basal ganglia) and white matter ( centrum semiovale) infarcts may develop distinctive clinical syndrome
  
  • Caused by
    ○ Multi-focal vascular disease of several types including
    § Cerebral atherosclerosis
    § Vessel thrombosis or embolisation from carotid vessels or the heart
    § Cerebral arteriolo-sclerosis from chronic hypertension

Question 24

Characteristics of vascular dementia

Answer 24

○ Dementia
○ Gait abnormalities
○ Pseudobulbar signs
○ Often with superimposed focal neurologic deficits

Question 25

What predisposing factors increase the likelihood of developing aspiration pneumonia?

Answer 25

- Reduced gag reflux or inability to maintain airway
		○ Alcoholism 
		○ Drug Overdose 
		○ Seizures
		○ Stroke
		○ Head Trauma 
		○ General Anaesthetic 
		○ Intracranial Mass Lesion 
	- Oesophageal conditions
		○ Functional dysphagia
		○ Strictures
		○ Neoplasm
		○ Tracheoesophageal fistula
		○ Diverticula
		○ GORD
	- Iatrogenic
		○ Nasogastric Tube 
		○ Endotracheal Intubation 
		○ Tracheostomy 
		○ Upper GI Endoscopy 
		○ Bronchoscopy 
		○ Gastrostomy 
		○ Post-pyloric Feeding Tube 
	- Neurological
		○ Multiple Sclerosis 
		○ Myasthenia Gravis 
		○ Dementia 
		○ Parkinson’s Disease 
		○ Pseudobulbar Palsy

Question 26

Organisms typically responsible in aspiration pneumonia

Answer 26

• Staphylococcus aureus
  
  • Haemophilus influenzae
  • Pseudomonas aeruginosa - intubation
  • Streptococcus pneumoniae

Question 27

Morphological features of aspiration pneumonia

Answer 27

- Gross
		○ Focal areas of consolidation
	- Micro
		○ Foreign body giant cells
		○ Presence of aspirated material

Question 28

Define pulmonary abscess

Answer 28

• Local suppurative process that produces necrosis of lung tissue

Question 29

Aetiology of pulmonary abscess

Answer 29

○ Commonly complication of aspiration pneumonia
○ Antecedent primary lung infection
○ Septic embolism
○ Neoplasia
○ Primary cryptogenic lung abscess - no identifying cause

Question 30

Morphology of pulmonary abscess

Answer 30

○ Gross
			§ Purulent exudate
			§ Hallow abscess cavities due to necrosis
		○ Micro
			§ Neutrophilic exudate
			§ Bacterial colonies

Question 31

Complications of pulmonary abscess

Answer 31

○ Empyema
○ Pneumothorax
○ Internal haemorrhage
○ Brain abscess

Question 32

Define osteopenia

Answer 32

○ Decreased bone mass

○ Bone mass 1-2.5 SDs below mean peak bone mass in young adults

Question 33

Define osteoporosis

Answer 33

○ Osteopenia that is severe enough to significantly increase fracture risk
○ Bone mass ≥ 2.5 SDs below mean peak bone mass in young adults

Question 34

Conditions associated with development of osteoporosis

Answer 34

- Primary osteoporosis - most common
		○ Idiopathic
		○ Post-menopausal - oestrogen deficiency
		○ Senile - aging skeleton and calcium deficiency
	- Associated conditions
		○ Endocrine
			§ Addison’s
			§ T1DM
			§ Hyperparathyroidism
			§ Hypothyroidism
			§ Tumours & metastasis
			§ Multiple myeloma
		○ Gastrointestinal
			§ Hepatic insufficiency
			§ Malabsorption
			§ Malnutrition
			§ Vitamin C & D deficiency 
		○ Drugs
			§ Alcohol
			§ Smoking
			§ Anticoagulants
			§ Anticonvulsants
			§ Chemotherapy
			§ Corticosteroids 
		○ Other
			§ Anaemia
			§ Homocystinuria
			§ Immobilisation
			§ Osteogenesis imperfecta
			§ Pulmonary disease

Question 35

Pathophysiology of osteoporosis

Answer 35

• Age-related changes
  ○ Reduced proliferative ability
  ○ Reduced response to growth factors of osteoblasts
  ○ Diminished ability to make bone
  ○ Low turnover osteoporosis
  
  • Physical inactivity
    ○ Increases bone loss
    ○ Mechanical forces needed to stimulate bone remodelling
    ○ Resistance exercises important in reducing bone loss
    ○ Contributes to senile osteoporosis
  • Oestrogen deficiency
    ○ Secretion of inflammatory cytokines, which increase RANKL and decrease OPG
    § Increases bone resorption
    ○ High turnover osteoporosis
  • Genetic factors
    ○ Single gene defects rare cause of osteoporosis
    ○ Polymorphisms in certain genes contribute to variation in peak bone density within populations
    ○ RANK, RANKL, OPG (osteoclast regulators)
    ○ Oestrogen receptor gene
  • Calcium
    ○ Contributes to peak bone mass
    ○ Adolescent girls have insufficient intake
    ○ If it occurs in period of rapid bone growth, calcium deficiency reduces peak bone mass and increases osteoporosis risk
    ○ Calcium and vit D deficiencies in older age may contribute to senile osteoporosis

Question 36

Morphological features of osteoporosis

Answer 36

• Hallmark: decreased quantity of histologically normal bone
  ○ Decreased bony spicules of decreased size from osteoporosis
  
  • Entire skeleton affected but certain bones tend to be more severely impacted
    ○ Hip, wrist and vertebrae most likely to fracture
  • Postmenopausal
    ○ Bones/portions of bones with increased surface area e.g. cancellous compartment of vertebral bodies
    ○ Cancellous bone become perforated and thinned, and lose their interconnections, leading to microfractures and vertebral collapse
  • Senile
    ○ Cortex thinned by subperiosteal and endosteal resorption, and the osteons are widened

Question 37

Process of fracture healing

Answer 37

• Primary healing- no callus, bone remodelling
  
  • Secondary healing:
    ○ Inflammation
    ○ Repair- soft and hard callus
    ○ Remodelling
  • Inflammation - haematoma (0-1 days)
    ○ Provides fibrin mesh- seals fracture site
    ○ provides a source of hematopoietic cells capable of secreting growth factors
    ○ Macrophages, neutrophils, and platelets release several cytokines
    ○ Stimulates osteoblasts and osteoclasts
    ○ Fibroblasts and mesenchymal cells migrate to fracture site and granulation tissue forms around fracture ends
  • Repair
    ○ Soft callus (within 2 weeks)
    § Uncalcified tissue
    § Stabilises fracture and creates a template for new bone to be laid down
    ○ Activated osteoprogenitor cells lay down woven bone -> bony callus
    § The osteoblasts and chondroblasts, synthesize woven bone and cartilage, and then the newly formed bone is mineralized (endochondral ossification).
    § This stage requires 4-16 weeks
  • Remodelling
    ○ Begins in middle of repair phase and carries on long after bone union
    ○ Conversion of woven bone into lamellar bone
  • Morphology
    ○ Broken ends of bone spicules
    ○ Callus formation
    ○ Areas of loose connective tissue and blood vessels