Neuropathology 1 cerebrovascular disease (pie)

Question 1

What are the different causes of nervous system injury ?

Answer 1

• Hypoxia
• Trauma
• Toxic insult
• Metabolic abnormalities
• Nutritional deficiencies
• Infections
• Genetic abnormalities
• Ageing

Question 2

What are the 2 main cellular responses to injury that damage to nerve cells &/or their processes can lead to ?

Answer 2

1. Rapid necrosis with sudden acute functional failure (as seen in “stroke”)
2. Slow atrophy with gradually increasing dysfunction (as seen in age-related cerebral atrophy)

Question 3

What is the typical appearance of acute neuronal injury and what is this commonly due to?

Answer 3

Occurs in the context of hypoxia / ischaemia and is typically visible 12-24 hours after an irreversible “insult” to the cell ==> Results in neuronal cell death

Appearance of neuron:

• Shrinking and angulation of nuclei
• Loss of the nucleolus
• Intensely red cytoplasm

Pic shows the appearance of a normal neuron compared to one which has undergone acute neuronal injury

Question 4

What are some of the other responses which can occur in neurons in response to insult?

Answer 4

Axonal reactions:

• Increased protein synthesis -> cell body swelling, enlarged nucleolus
• Chromatolysis – margination and loss of Nissl granules
• Degeneration of axon and myelin sheath distal to injury “Wallerian degeneration”

Simple neuronal atrophy (chronic degeneration):

• Shrunken, angulated and lost neurons, small dark nuclei, lipofuscin pigment, reactive gliosis

Sub-cellular alterations – inclusions:

• Common in neurodegenerative conditions, e.g. neurofibrillary tangles in Alzheimer’s disease
• Inclusions appear to accumulate with ageing
• Also get inclusion in viral infections affecting the brain

Question 5

Define what is meant by the term gliosis

Answer 5

• Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS).
• In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes.

Question 6

What is the typical response seen in astrocytes in response to CNS injury of any cause ?

Answer 6

In early gliosis:

• Astrocytes undergo hyperplasia and hypertrophy i.e. they grow in number and size
• They get enlarged vesicular nuclei and prominent nucleoli
• Cytoplasmic expansion with extension of ramifying processes

In older gliosis:

• In old lesions, such as at the edge of an old infarction – nuclei become small and dark and lie in a dense net of processes (glial fibrils)

Question 7

What is the most important histopathological indicator of CNS injury, regardless of cause?

Answer 7

Astrocytic Reponse

Question 8

Describe the response of oligodendrocytes to injury

Answer 8

They are less sensitive than neurones so often have a limited reaction to injury, due to having low anti-oxidant reserves and high intracellular iron, they are sensitive to oxidative stress, and will die in response to significant hypoxic injury.

Question 9

What is oligodendorycte damage a feature of ?

Answer 9

Demyelinating disorders

Question 10

What is the response of microglia cells in response to CNS injury ?

Answer 10

Recall the function as the macrophage system in the CNS

Response to injury:

• Microglia proliferate
• Recruited through inflammatory mediators
• Form aggregates
• Around areas of necrotic and damaged tissues

Question 11

What is the most vulnerable CNS cell to hypoxic injury and why ?

Answer 11

Neurons because they are so metabolically dependent on oxidative phosphorylation

Question 12

What are some of the causes of hypoxic brain injury ?

Answer 12

• Cerebral ischaemia, infarct, haemorrhages, trauma, cardiac arrest, cerebral palsy
• After onset of ischaemia, mitochondrial inhibition of ATP synthesis leads to ATP reserves being consumed within a few minutes ==> neurons damaged

Question 13

What happens when the autoregulatory mechanisms of the brain which help maintain blood flow at a constant rate by dilatation and constriction of cerebral blood vessels ?

Answer 13

Results in hypoxic brain injury in ischemia leading to infarction.

Question 14

Define cerebrovascular disease and what are the common causes of it ?

Answer 14

Any abnormality of brain caused by a pathological process of blood vessels

This includes:

• Brain ischaemia and infarction
• Haemorrhages
• Vascular malformations
• Aneurysms

Question 15

What is the commonest cause of disability in Scotland ?

Answer 15

Cerebrovascular disease

Question 16

What are the 2 processes that cerebrovascular disease involves ?

Answer 16

1. Hypoxia, ischaemia and infarction resulting from impairment of blood supply and oxygenation of tissue
2. Haemorrage resulting from rupture of CNS vessels, in this case a SAH resulting from a ruptured berry aneurysm

Question 17

What can cerebral ischaemia be classified into and what are the causes ?

Answer 17

Can be classified as global or focal

Global hypoxic ischaemic damage - when the systemic compromise to circulation that cannot be compensated for by CNS auto-regulatory mechanisms

• Generalised reduction in blood flow / oxygenation
• Cardiac Arrest
• Severe hypotension, e.g. trauma with hypovolaemic shock

Focal - restriction of blood to a certain area of brain

• Vascular obstruction

Question 18

When does global ischaemia occur to the brain ?

Answer 18

• If there is a generalised reduction of cerebral perfusion Mean arterial pressure below 50mmHg and autoregulatory mechanisms cannot sufficiently compensate
• Watershed areas at the periphery of a vascular territories contain neurons particularly sensitive to hypoxia, because they are the most distant from the heart and least well supplied
• Neurons more sensitive than glial cells, and some neurons are more sensitive than others - Neocortex and hippocampus areas particularly sensitive
• Severe ischemia leads to pan-necrosis

Question 19

Go over the pathological stages following a cerebral infarction

Question 20

At 48hrs following a cerebral infarction what change in cell type is the main feature ?

Answer 20

Neutrophil infiltration drops off after 48 hours and microglia gradually become the predominant cell type present

Question 21

After a week following a cerebral infarction what histological process starts to occur ?

Answer 21

Reactive gliosis occurs in which astrocytes increase in number and size

Question 22

After a few weeks following a cerebral infarction what begins to form ?

Answer 22

• A cavity begins to form which is lined by a gliotic scar characterised by astrocytes with abundant fine cytoplasmic processes.
• Eventually, even the gliotic scar desists and a cystic gap remains as a permanent marker of the site of an old infarction

Question 23

What are the changes HTN causes in the brain ?

Answer 23

• Accelerated atherosclerosis - contributes to thromboembolism
• Lacunes - Lacunae are by definition lake like infarcts of less than 15mm maximum diameter. They occur when there is occlusion of a small penetrating vessel such as is seen due to occlusion of part of a lenticulostriate artery
• Hyaline arteriolosclerosis - results in thinning and weakening of small vessel walls making them more prone to occlusion and to rupture.
• Micro-aneurysms (Charcot-Bouchard)

Question 24

What are the consequences of the changes HTN causes on the brain ?

Answer 24

• Lacunar infarcts - Atheroma, embolism small penetrating vessels leads to occlusionBasal ganglia
• Multi-infarct dementia
• Ruptured aneurysms and intra-cerebral haemorrhage
• Hypertensive encephalopathy - PM: global cerebral oedema, tentorial and tonsillar herniation, petechiae and arteriolar fibrinoid necrosis

Question 25

What is the most common cause of sub-arachnoid haemorrhage and what are the 2 most common locations for them to form ?

Answer 25

Berry aneurysms

They arise at arterial bifurcations typically in the region of:

• 90% in territory of internal carotid artery
• 10% in vertebro-basilar circulation