Neuropathology 1: Cerebrovascular Disease

Question 1

Why are most disease processes in the brain not considered benign?

Answer 1

Brain is contained within the rigid cranium that does not allow for V increase; so, P increases as a consequences

Question 2

What are bridging veins?

Answer 2

Vessels that course through the subarachnoid space and, adjacent to the sagittal-midline veins, perforate the arachnoid and dura

Question 3

Cellular components of the CNS?

Answer 3

Neurones (nerve cells) - key communicating cells

Glial cells - derived from the neuroectoderm and provide support for neurones and their dendritic and axonal processes:
• Astrocytes - provide the brain with a fixed, 3D structure to support other CNS cells; these cells are closely coupled, functionally, with neurones
• Oligodendrocytes - wrap around axons, forming the myelin sheath
• Ependymal cells - line the ventricular system

Microglia (derived from the mesoderm) - originate in the bone marrow and serve as a macrophage system

Supporting structures:
• Connective tissue
• Meninges
• Blood vessels

Question 4

Pathologies assoc. with all glial cells?

Answer 4

May all give rise to tumours within the brain

Question 5

Causes of NS injury?

Answer 5

HYPOXIA - lack of oxygen or no oxygen (anoxia) of brain parenchyma; this is often a phenomenon that occurs secondary to other insults

Trauma - direct, avulsion / axotomy of neurones

Toxic insult, metabolic abnormalities, nutritional deficiencies

Infections

Genetic abnormalities

Ageing

Question 6

How do cells respond to injury?

Answer 6

Damage to nerve cells and/or their processes can lead to:
• RAPID necrosis with sudden acute functional failure, e.g: this occurs in stroke
OR
• SLOW atrophy with gradually increasing dysfunction, e.g: this occurs in age-related cerebral atrophy

Question 7

When does acute neuronal injury occur?

Answer 7

Represents a lethal injury to the neurone, typically caused by ischaemia or hypoxia, e.g: in the context of a stroke

Results in neuronal cell death

Changes are typically visible 12-24 hours after an irreversible insult to the cell

Question 8

What are red neurones?

Answer 8

Describes what an acutely injured and dying neuronal cell body looks like; features include:
• Shrinking and angulation of nuclei
• Loss of the nucleolus
• Intensely red cytoplasm (eosinophilia)

If this can be seen, it indicates that that he underlying cause is of an acute hypoxic nature

Question 9

What other neuronal responses occur to injury / disease?

Answer 9

Axonal reactions - a neuronal cell body reaction assoc. with axonal injury

Simple neuronal atrophy - occurs in diseases of long duration, e.g: MS or Alzheimer’s

Sub-cellular alterations - to neuronal organelles and cytoskeleton; it is common in neurodegenerative conditions

Question 10

Pathology of axonal reactions?

Answer 10

Increased protein synthesis leads to:
• Cell body swelling
• An enlarged nucleus

Chromatolysis (margination and loss of Nissl granules)

Wallerian degeneration - degeneration of axon and myelin sheath distal to injury

Question 11

Difference in axonal reactions that occur in the CNS and in the PNS?

Answer 11

In the PNS, there is often preservation of the myelin sheath to form a neural tube that can afford some regeneration

Question 12

Pathology of simple neuronal atrophy?

Answer 12

Shunken neurones and neuronal loss; depending on the case, simple neuronal atrophy often affects functionally related neurones

Lipofuscin pigmentation

It is often assoc. with reactive gliosis

Question 13

Situations where sub-cellular alterations to the neuronal organelles and cytoskeleton occur?

Answer 13

Includes:
• Neurofibrillary tangles in Alzheimer’s disease
• Lewy bodies in Lewy Body dementia and Parkinson’s disease
• Neural inclusions in ageing
• Intranuclear and cytoplasmic inclusions in viral diseases

Question 14

Structure of astrocytes?

Answer 14

Star-shaped cells with multipolar cytoplasmic processes

Astrocytic processes:
and includes:
• Envelop synaptic plated
• Wrap around vessels and capillaries within the brain

Question 15

Location of astrocytes?

Answer 15

Present throughout the CNS

Astrocytic processes envelop synaptic plates and wrap around vessels and capillaries within the brain

Question 16

Function of astrocytes?

Answer 16

Ionic, metabolic and nutritional homeostasis

Work in conjunction with endothelial cells to maintain the BBB

Foot processes wrap around intracerebral small vessels and capillaries (regulate cerebral blood flow)

Main cell inv. in repair and scar formation, given the lack of fibroblasts

Question 17

Why are astrocytes metabolically coupled to neurones?

Answer 17

Astrocytes do anaerobic glycolysis, while neurones do not; they produce lactate, which is transferred to the neurone for use as a metabolite for the production of ATP

Question 18

What is gliosis?

Answer 18

It is an astrocytic response and is the MOST IMPORTANT histopathological indicator of CNS injury, regardless of cause

Question 19

Histopathology of gliosis?

Answer 19

Astrocyte hyperplasia and hypertrophy (increased no. and size)

Nucleus enlarges and becomes vesicular; the nucleolus becomes prominent

There is cytoplasmic expansion with extension of ramifying processes

Question 20

Histopathology of old lesions?

Answer 20

E.g: an area of gliosis in an old infarct

Nuclei become small and dark and lie in a dense net of processes (glial fibrils)

Question 21

Oligodendrocyte response to injury?

Answer 21

Relatively limited reaction to injury:
• Variable patterns and degrees of demyelination
• Apoptosis

NOTE - oligodendrocyte damage is a feature of demyelinating disorders, leading to abnormalities in neuronal conduction

Question 22

Oligodendrocytes are sensitive to which type of injury?

Answer 22

Oxidative damage; they die in respose to significant hypoxic injury

Question 23

Conduction of membrane depolarisations?

Answer 23

Jump from one node of Ranvier to the next through saltatory conduction

Question 24

What happens when there is axonal damage?

Answer 24

Wallerian degeneration - antegrade degeneration of the axon to the nearest node of Ranvier

Question 25

Ependymal cell reaction to injury?

Answer 25

Limited reaction to injury; infectious agents, inc. viruses, produce changes in ependymal cells Disruption of these cells is often assoc. with a local proliferation of sub-ependymal astrocytes; these produce small irregularities on the ventricular surfaces, referred to as EPENDYMAL GRANULATIONS

Question 26

Microglia response to injury?

Answer 26

Microglia proliferate and are recruited via inflammatory mediators; they form aggregates around areas of necrotic and damages tissues

Question 27

Types of microglia?

Answer 27

M2 - anti-inflammatory and phagocytic, mainly cleaning up at the centre of acute damage M1 - pro-inflammatory and appear later after acute injury (more chronic); they can exacerbate aspects of acute brain injury and are important mediators of, e.g: Alzheimer's disease and MS

Question 28

What is the most important base-line cause of neuronal injury?

Answer 28

``` Hypoxia; causes include: • Cerebral ischaemia • Infarct • Haemorrhages • Trauma • Cardiac arrest • Cerebral palsy ```

Question 29

What happens when ischaemia occurs in the brain?

Answer 29

After onset of ischaemia, mitochondrial inhibition of ATP synthesis leads to ATP reserves being consumed within a few minutes

Question 30

Explain how excitotoxicity is responsible for acute neuronal injury?

Answer 30

NOTE - mainly caused by HYPOXIA and the secondary brain injury that follows trauma In the above cases, there is energy failure and: • Neural depolarisation leads to glutamate release • Astrocyte reuptake is inhibited and this leads to a failure of glutamate reuptake Above issues lead to a glutamate storm and excitation There is uncontrolled Ca2+ entry into cells, leading to: • Protease activation • Mitochondrial dysfunction • Oxidative stress Apoptosis and necrosis occurs

Question 31

Types of oedema and situations where they occur?

Answer 31

Cytotoxic oedema - a pre-morbid process that occurs in: • Intoxication • Reye's • Severe hypothermia ``` Ionic oedema (AKA osmotic oedema) occurs in: • Hyponatraemia and excess water intake (e.g: SIADH) ``` Vasogenic oedema: • MAINLY occurs in trauma, tumours and inflammation • Also in infection • Hypertensive encephalopathy

Question 32

Pathology of cytotoxic oedema?

Answer 32

Dying cells accumulate water (pre-morbid condition) as osmotically active EC ions, like Na+ and Cl-, move into cells and take water with them In isolation, cytotoxicity of itself does not cause swelling; however, cytotoxic oedema can enhance ionic and vasogenic oedema

Question 33

Pathology of ionic oedema?

Answer 33

1st dysfunction of the BBB Occurs due to cytotoxic oedema, which results in the EC space being relatively devoid of Na+ Na+ ions cross the BBB and thus drive Cl- transport, creating an osmotic gradient for water accumulation Gives rise to swelling

Question 34

Pathology of vasogenic oedema?

Answer 34

Occurs along with deterioration and breakdown in the BBB Due to disruption of endothelial tight junctions, plasma proteins (like albumin) cross into the EC space; these are potent osmotic factors, so water follows NOTE - disruption of the BBB is not severe enough to allow passage of rbcs

Question 35

What is haemorrhagic conversion?

Answer 35

Occurs when endothelial integrity is completely lost and blood can enter the EC space Such extravasation of rbcs occurs in 30-40% of ischaemic strokes

Question 36

Areas of the cerebral circulation commonly affected by thromboembolic disease?

Answer 36

Alignment of the internal carotid artery and middle cerebral artery (MCA) helps to explain why the MCA is more commonly affected by thromboembolic disease There is angular branching in the cerebral circulation; branching points often have turbulent flow, increasing risk of endothelial damage, vessel weakening and variable extent of atherosclerosis

Question 37

Arteries supply which parts of the brain?

Answer 37

ACA - midline portions of the frontal and superior medial parietal lobes ``` MCA (arises from internal carotid artery): • Lateral sulcus • Lateral cerebral cortex • Anterior temporal lobes • Insular cortices ``` PCA - occipital lobe (posterior aspect of the brain)

Question 38

Responsibilities of the anterior cerebral artery territory? i.e: where would symptoms manifest if an issue arose within the ACA

Answer 38

Sensory and motor abnormalities in the trunk and legs Frontal lobe dysfunction Higher cognitive dysfunction

Question 39

Responsibilities of the middle cerebral artery territory? i.e: where would symptoms manifest if an issue arose within the MCA

Answer 39

Major bulk of the sensory and motor cortex

Question 40

Responsibilities of the posterior cerebral artery territory? i.e: where would symptoms manifest if an issue arose within the PCA

Answer 40

Occipital lobes affected, leading to a left OR right homonymous hemianopia (visual field defect will be on the same side as the lesion)

Question 41

Define cerebrovascular disease?

Answer 41

Any abnormality of brain caused by a pathological process of blood vessels It is the most common cause of adult disability

Question 42

Types of cerebrovascular disease?

Answer 42

Brain ischaemia and infarction: • Ischaemic stroke • Occlusion of veins / sinuses can lead to P changes, preventing tissue perfusion and leading to ischaemia and infarction Haemorrhages Vascular malformation, e.g: AVM s Aneurysms NOTE - Berry aneurysms can result in acute haemorrhage

Question 43

2 processes that are essentially inv. in cerebrovascular disease?

Answer 43

1. Hypoxia, ischaemic and infarction lead to impaired blood supply and tissue oxygenation 2. Haemorrhage, resulting from CNS vessel rupture

Question 44

An important process that overlaps with both?

Answer 44

Hypertension causing hypertensive cerebrovascular disease

Question 45

Classifications of cerebral ischaemia?

Answer 45

Global hypoxic ischaemic damage - systemic compromise to circulation (generalised decrease in blood flow / oxygenation) that cannot be compensated for by CNS auto-regulatory mechanisms, e.g: • Cardiac arrest • Severe hypotension, like in hypovolaemic shock Focal ischaemia - restriction of blood flow to a localised area of the brain, e.g: • Vascular obstruction

Question 46

Consequences of global hypoxic ischaemic damage?

Answer 46

Generalised reduction in cerebral perfusion, due to: • Cardiac arrest • Shock / severe hypotension • Trauma Autoregulatory mechanisms can no longer compensate Severe ischaemia can cause pan-necrosis

Question 47

Which areas of the brain are part. sensitive to hypoxic ischaemic damage?

Answer 47

WATERSHED AREAS - at the periphery of vascular territories, there are neurones that are part. sensitive to hypoxia (most distant from the heart and so least well supplied)

Question 48

Which cells are most sensitive to hypoxic ischaemic damage?

Answer 48

Neurones are more sensitive than glial cells, i.e: neurones are injured first

Question 49

Which neurones are more sensitive than others to hypoxic ischaemic damage?

Answer 49

Neurones of the neocortex and hippocampus Purkinje cells of the cerebellum

Question 50

What is a stroke?

Answer 50

Sudden disturbance of cerebral function of vascular origin that causes death or lasts >24 hours

Question 51

Types of stroke?

Answer 51

Infarction (most common): • Thrombotic (in an atherosclerotic segment; most common in the MCA) • Embolic (from an atheroma in the internal carotid artery and carotid arch OR from the heart) Haemorrhage: • Intracerebral • Subarachnoid • Bleeding into an infarct

Question 52

Cause of cerebral infarction?

Answer 52

Interruption of cerebral blood flow due to thrombosis or emboli

Question 53

Occurrence of cerebral infarction?

Answer 53

Peak age of incidence >70 years More common in men than women

Question 54

Where do emboli to the cerebrum come from?

Answer 54

From an atheroma in the internal carotid artery From the heart NOTE - mainly occlude the MCA

Question 55

Rare causes of cerebral infarction?

Answer 55

Osteophytes compromising the vascular circulation Vasculitis

Question 56

Risk factors for stroke?

Answer 56

Atheroma in the intracranial (basilar artery the a main artery that is part. affected) and extracranial vessels Hypertension (this is a risk factor for atheroma anywhere and also causes changes in cerebral vessel walls) Serum lipids, obesity, diet DM Heart disease Disease of neck arteries Drugs and smoking

Question 57

Location, destruction and extent of parenchymal damage caused by a cerebral infarction are determined by?

Answer 57

1. Arterial territory of the affected artery 2. Timescale of the occlusion 3. Extent of collateral circulatory relief 4. Systemic perfusion pressure

Question 58

Microscopic progression of cerebral infarction?

Answer 58

0-12 hours - little visible pathology 12-24 hours - red neurones, oedema (cytotoxic and vasogenic) with generalised cell swelling 24-48 hours: • Increased NEUTROPHILS • Extravasation of rbcs (haemorrhagic conversion) • Activation of astrocytes and microglia 2-14 days - neutrophil infiltration drops after 48 hours and MICROGLIA become the predominant cell type: • Phagocytose myelin, i.e: myelin breakdown • Reactive gliosis begins as early as 1 WEEK Several months - ongoing phagocytosis increases cavitation and surrounding GLIOTIC SCAR formation

Question 59

When does the necrotic area becoming macroscopically visible, following cerebral infarction?

Answer 59

After >48 hours

Question 60

When does gliosis begin following a cerebral infarction?

Answer 60

Reactive gliosis occurs (astrocytes increase in no. and size)

Question 61

Macroscopic appearance of an old cerebral infarction?

Answer 61

Eventually, even the gliotic scar desists and a cystic gap remains as a permanent marker of the old infarction

Question 62

Causes of haemorrhagic infarcts?

Answer 62

1. BBB disruption or deterioration, e.g: in the context of vasogenic oedema (haemorrhagic conversion) and ischaemia 2. Haemorrhagic conversion - loss of endothelial integrity and entry of blood into the EC space; this extravasation of RBCs occurs in some ischaemic strokes 3. Thrombolysis - reperfusion can result in leakage through a damaged capillary bed, following lysis of the embolus

Question 63

Signs of specific vascular lesion and how these can be used to localise the site of the lesion?

Answer 63

Carotid artery disease: • Contralateral weakness or sensory loss • If affecting the dominant hemisphere, may have aphasia (inability to comprehend and formulate language) or apraxia MCA - weakness mainly in the contralateral face and arm ACA - weakness and sensory loss in the contralateral leg ``` Vertebro-basilar artery disease: • Vertigo • Ataxia • Dysarthria (slurred or slow speech) • Dysphasia ( deficiency in the generation of speech) • Complex brain stem syndromes ```

Question 64

What is apraxia?

Answer 64

Problems saying sounds, syllables, and words This is not because of muscle weakness / paralysis Brain has problems planning to move the body parts, e.g: lips, jaw, tongue, needed for speech

Question 65

Effects of hypertension on the brain?

Answer 65

Accelerated atherosclerosis - contributes to thromboembolism Lacunes - CSF-filled cavities in the basal ganglia Lacunar infarcts - atheroma or embolism in small, penetrating vessels leads to occlusion; tends to occur in basal ganglia Multi-infarct dementia Hyaline arteriosclerosis - thinning and weakening of small vessel wall, so more prone to occlusion and rupture Micro-aneurysms (AKA Charcot-Bouchard) - mainly occur in small MCA branches; rupture leads to intracerebral haemorrhage Hypertensive encephalopathy - occurs in severe hypertensives in whom autoregulatory mechanisms are saturated

Question 66

Pathology of hypertensive encephalopathy?

Answer 66

Global cerebral (vasogenic) oedema - BBB becomes incapable of resisting movement of plasma proteins (albumin) and water Tentorial and tonsilar herniation Petechiae Arteriolar fibrinoid necrosis

Question 67

Occurrence and meaning of lacunar infarcts?

Answer 67

Not infrequent incidental findings on radiology / post-mortem, with no apparent clinical correlate However, e,g: a small lacunar infarct affecting the internal capsule can cause extensive motor weakness, inc. in the face, arm and leg

Question 68

Consequences of lacunar infarcts?

Answer 68

Can contribute to multi-infarct dementia

Question 69

Types of intracranial haemorrhage?

Answer 69

SPONTANEOUS: • Intracerebral haemorrhage • Sub-arachnoid haemorrhage • Haemorrhagic infarct ``` TRAUMATIC: • Extra-dural haematoma • Sub-dural haematoma • Contusion (surface bruising of the brain) • Intracerebral haemorrhage • Sub-arachnoid haemorrhage ```

Question 70

Factors other than trauma and spontaneity that contribute to intracerebral haemorrhage?

Answer 70

Hypertension Aneurysms Systemic coagulation disorders Anti-coagulation Vascular malformations Amyloid deposits (cerebral amyloid angiopathy) Open heart surgery Neoplasms Vasculitis (infectious and non-infectious)

Question 71

Locations where intracerebral haemorrhage can occur?

Answer 71

Most commonly in the BASAL GANGLIA Thalamus, cerebral white matter and cerebellum as well

Question 72

Gross appearance of a brain affected by intracerebral haemorrhage?

Answer 72

Brain is asymmetrically distorted by the mass effect of the haemotoma and assoc. oedema Softening of adjacent tissue NOTE - unlike infarcts with secondary haemorrhage, there is no necrosis present within the area of haemorrhagic change

Question 73

In which conditions does amyloid angiopathy occur?

Answer 73

Alzheimer's disease Also occurs as an age-related change

Question 74

Pathology of amyloid angiopathy?

Answer 74

β-amyloid forms tightly packed β-pleated sheets, which are deposited within the cerebral and meningeal vessels Thus, vessels become less compliant and cannot deal with localised increases in P; they can rupture as a result, classically causing a local intracerebral haemorrhages

Question 75

Types of vascular malformations?

Answer 75

Arteriovenous malformations (AVMs) - most likely to be assoc. with a clinically significant haemorrhage; these have a major re-bleed rate Cavernous angiomas - some patient have a clinically significant haemorrhage Venous angiomas Capillary telangectases

Question 76

Clinical signs and symptoms of vascular malformations?

Answer 76

Headaches, seizures and focal neurological deficits When they bleed, other symptoms occur

Question 77

Locations of AVMs?

Answer 77

Most common in the cerebral hemispheres, specifically in the MCA territory

Question 78

How do AVMs rupture?

Answer 78

Shunting of blood from artery to vein leads to the vein undergoing smooth muscle hypertrophy; it is no longer compliant and easily ruptures Also, forms aneurysms, which may rupture

Question 79

Appearance of AVMs?

Answer 79

Conglomerate of abnormal, tortuous vessels

Question 80

Types of sub-arachnoid haemorrhage?

Answer 80

Spontaneous OR traumatic

Question 81

Most common cause of sub-arachnoid haemorrhage?

Answer 81

Rupture of a Berry (sacular) aneurysm: • In the territory of the internal carotid artery (90%) • Vertebro-basilar circulation (10%)

Question 82

Locations from which sub-arachnoid haemorrhages arise?

Answer 82

Arterial bifurcations in the territory of the ICA, typically at bifurcations arising from the circle of Willis

Question 83

Greatest risk of saccular aneurysm rupture is at what size?

Answer 83

Enlarge with time and are at great risk of rupture at a diameter of 6-10mm In aneurysms >25mm diameter, risk of rupture decrease (due to the mass effect predominating)

Question 84

Consequences of sub-arachnoid haemorrhage assoc. with aneurysm rupture?

Answer 84

Intacerebral haematomas adjacent to the aneurysms, i.e: due to high P involved, there is assoc. intracerebral haemorrhage Infarcts of brain parenchyma may develop (due to arterial spasm causing vasoconstriction and decreased blood supply) Mass effect of haematoma can lead to features of raised ICP Hydrocephalus (due to obstruction of CSF flow in sub-arachnoid space) is a risk in in survivors

Question 85

Risk factors for aneurysm rupture?

Answer 85

Smoking Hypertension Autosomal dominant polycystic kidney disease (ADPKD) More common in women Usually <50 years

Question 86

Clinical presentation of sub-arachnoid haemorrhage, due to a ruptured aneurysm?

Answer 86

Abrupt onset of severe headache, vomiting and LoC Usually no Hx of a precipitating factor