W7 33 neuropathology

Question 1

How does raised intracranial pressure occur?

Answer 1

Relatively minor changes in the composition of the tissue can affect the pressure within the brain, and since contained by the tight skull cavity, can lead to significant pressure alterations, manifesting as diseases.

Question 2

What are some causes of raised intracranial pressure?

Answer 2

Head injury/haemorrhage
Infection
Neoplasia
Hydrocephalus
Cerebral oedema

Question 3

What is hydrocephalus?

Answer 3

Obstruction to the flow of CSF, leading to compression of brain and expansion of ventricles

Question 4

What is cerebral oedema and how does it occur?

Answer 4

Accumulation of fluid in the brain, a response to either:
- vasogenic injury (causing increased vascular permeability)
- cytotoxic damage (injury to neuron/glial membranes)

Question 5

What are the effects of raised intracranial pressure?

Answer 5

Headache, vomiting, seizures
Reduced conscious level
Papilloedema (changes in retina)
Herniation

Question 6

What is herniation?

Answer 6

Protrusion of one part of the brain into another compartment

Question 7

What are the 3 types of herniation and where are their sites of lesion? (IMG PP341)

Answer 7

Subfalcine (cingulate) - frontal lobe
Transtentorial (uncinate) - lateral supratentorial
Tonsillar - posterior fossa

Question 8

Which herniation cause significant clinical problems?

Answer 8

Transtentorial and tonsillar herniations can cause significant clinical problems
Subfalcine herniation doesn’t usually cause symptoms

Question 9

Why does subfalcine herniation not usually cause clinical problems and what is the exception to this?

Answer 9

Because the frontal lobe is involved in higher cortical functions, so damage to a small area has limited clinical consequences, so usually clinically silent
Exception if the anterior cerebral artery (ACA) becomes compressed, which can cause a stroke

Question 10

What are the effects of transtentorial herniation?

Answer 10

Compression of third cranial nerve
Compression of posterior cerebral artery
Compression of contralateral cerebral peduncle
Tearing of vessels in upper brainstem

Question 11

Transtentorial hernation can cause compression of the third cranial nerve. What can this lead to?

Answer 11

Ipsilateral pupillary dilatation
Ophthalmoplegia

Question 12

Transtentorial hernation can cause compression of the posterior cerebral artery. What can this lead to?

Answer 12

Ischaemia to visual cortex, so visual disturbance

Question 13

Transtentorial hernation can cause compression of the contralateral cerebral peduncle. What can this lead to?

Answer 13

Ipsilateral hemiparesis (false localising sign)
(normally hemiparesis occurs on the opposite side of the body to where the lesion in the brain is due to crossing fibres, but in transtentorial herniation, the contralateral cerebral peduncle might be compressed and be on the contralateral side to the lesion)

Question 14

Transtentorial hernation can cause tearing of vessels in the upper brainstem. What can this lead to?

Answer 14

Due to mechanical effects of herniation through the small aperture
Duret haemorrhage

Question 15

What are the effects of tonsillar herniation?

Answer 15

(where the brainstem extends through the foramen magnum)
Ataxia (due to damage to cerebellum)
Sixth nerve palsy
Brainstem compression - severe since respiratory rate and autonomic function are maintained here

Question 16

What are the types of traumatic brain injury?

Answer 16

Parenchymal tissue damage
Vascular tissue damage

Question 17

What can parenchymal tissue damage cause?

Answer 17

Concussion
Contusions
Diffuse axonal injury

Question 18

What can vascular tissue damage cause?

Answer 18

Epidural haematoma
Subdural haematoma
Subarachnoid haemorrhage
Intraparenchymal haemorrhage

Question 19

What is a concussion?

Answer 19

An abrupt transient loss of consciousness caused by massive short-lived increased intra-cranial pressure leading to temporary neuronal dysfunction; full recovery but with amnesia

Question 20

What is contusion?

Answer 20

Contusion = bruising. Results in pathological appearance of brain.

Question 21

What is coup contusion and contrecoup contusion?

Answer 21

Coup contusion = bruising due to striking of brain against bone at point of impact
Contrecoup contusion = bruising due to striking against bone opposite to point of impact

Question 22

What is diffuse axonal injury?

Answer 22

Form of acceleration/deceleration injury eg in RTA, leading to widespread tearing of axons

Question 23

What is epidural haematoma?

Answer 23

Accumulation of arterial blood between inner skull surface and dura

Question 24

What is the pathogenesis of an epidural haematoma?

Answer 24

Usually due to skull fracture damaging artery in dura
The middle meningeal artery is particularly susceptible

Question 25

What is the presentation of an epidural haematoma? (IMG PG345)

Answer 25

Lucid interval for several hours followed by progressive neurological impairment

Question 26

What is a subdural haematoma? (IMG PG345)

Answer 26

Accumulation of venous blood between the dura and outer surface of the arachnoid membrane

Question 27

What is the pathogenesis of subdural haematoma?

Answer 27

Rupture of bridging veins or sinuses in the subdural space. May be seen with only mild trauma, particularly in the elderly (with fragile vein walls)

Question 28

What is the presentation of subdural haematoma?

Answer 28

Focal neurological signs Personality change, confusion etc (non specific)

Question 29

What is a stroke?

Answer 29

Rapidly developing signs of focal (at times global) disturbance of cerebral function, lasting more than 24hrs or leading to death with no apparent cause other than that of vascular origin.

Question 30

What are signs of focal disturbance of cerebral function called if they last less than 24 hours?

Answer 30

Less than 24hrs are transient ischaemic attacks - TIAs

Question 31

Are ischaemic or haemorrhagic strokes more common? (Image of each pg346)

Answer 31

Ischaemia (85%) are more common than haemorrhagic (15%)

Question 32

What are the causes and risk factors of these causes for ischaemic stroke?

Answer 32

Thromboembolism from atherosclerosis in carotid artery and aortic arch (most common) - RF= hypercholesterolaemia, hypertension, smoking Thromboembolism from cardiac thrombi - RF= atrial fibrillation, MI Thrombosis/thromboembolism from atherosclerosis in small perforating intra-cerebral vessels - RF= hypercholesterolaemia, hypertension, smoking Other - vasculitis, endocarditis, cerebral venous disease

Question 33

What happens when cerebral perfusion falls?

Answer 33

Initially when perfusion pressure falls, the cerebral blood vessels dilate, and that can maintain the blood flow to the brain despite falling perfusion pressure. Only works to a certain point, if pressure continues to fall, blood flow itself to the tissue will fall too.

Question 34

What is the haemostatic response to falling perfusion (past certain point)? (PG347 IMG)

Answer 34

If pressure continues to fall, blood flow to the tissue will continue to fall too. The neurones use various metabolic processes to extract more oxygen out of the blood, to maintain oxygen metabolism despite reduced blood flow. However only has a limited ability to compensate, and if there is a further fall in perfusion pressure, oxygen metabolism starts to decrease, and the cells become ischaemic, and cells are compromised. This gives rise to symptoms, and the changes are reversible at this stage.

Question 35

What happens if the blockage is removed?

Answer 35

If the blockage id removed at an earlier point, the neurone can recover from the damage and the patient won’t have lasting effects, generally what occurs in a TIA. After a certain point, the damage to neurones becomes irreversible.

Question 36

What are the mechanisms of neuronal ischaemia? (PG348 LOOK AT IMG!)

Answer 36

1. Thromboembolism causes neuronal ATP depletion - reduced oxygen and glucose delivery to cells results in anaerobic metabolism with less ATP production 2. Failure of the Na+/K+ ATPase causes cell swelling and increased intracellular calcium 3-5. Glutamate release from glial cells release activates destructive intracellular enzymes. 6. Glial cells take up excess H+ (generated as a result of anaerobic metabolism) and thus can no longer absorb extracellular glutamate present in the synaptic areas, so glutamate can accumulate and interact with the neurones to cause further damage, with end result cell death.

Question 37

What is an MCA infarct?

Answer 37

Thrombus in the middle cerebral artery

Question 38

What is the morphology of acute ischaemic stroke? (Pg348 img)

Answer 38

Dusky discolouration of affected grey matter Blurring of cortical margins Swelling with midline shift

Question 39

What is a haemorrhagic transformation of ischaemic stroke?

Answer 39

Secondary haemorrhage into a bland ischaemic infarct (pre-existing ischaemic stroke)

Question 40

What is the pathogenesis of haemorrhagic stroke?

Answer 40

Happens due to ischaemic damage to vascular endothelium, blood leaks out causing haemorrhage.

Question 41

What are the risk factors for haemorrhagic stroke?

Answer 41

Large infarct Antithrombotic medication eg warfarin Thrombolytic drugs

Question 42

What are causes of haemorrhagic stroke?

Answer 42

Hypertension Cerebral amyloid angiopathy

Question 43

How does hypertension cause haemorrhagic stroke?

Answer 43

Causes a rupture of small intraparenchymal blood vessels Typically affects basal ganglia, thalamus, pons and cerebellum (brainstem and lower parts of brain)

Question 44

How does cerebral amyloid angiopathy cause haemorrhagic stroke?

Answer 44

Deposit in of amyloidogenic peptides in walls of blood vessels of the brain This weakens them predisposing to rupture Typically affects lobes of cerebral cortex

Question 45

What considerations are there for inflammation and healing following stroke?

Answer 45

Neurones are permanent cells Scarring is mediated by gliosis rather than fibrosis

Question 46

What occurs at different time frames for inflammation and healing following a stroke?

Answer 46

12-24 hrs - acute neuronal injury (cytoplasmic swelling and eosinophilia), liquefaction necrosis, acute inflammation 24hrs-2weeks - macrophage infiltration and phagocytosis 2weeks-2 months - phagocytosis of necrotic tissue, astrocytes proliferation Several months - cavity formation surrounded by rim of gliosis

Question 47

What are the components of the glial scar?

Answer 47

Astrocytes Cytokines secretion by microglia Angiogenesis

Question 48

What do astrocytes do in the glial scar?

Answer 48

Hypertrophy and hyperplasia with formation of numerous branching cell processes. They secrete extracellular matrix proteins.

Question 49

What does cytokine secretion by microglia do in a glial scar?

Answer 49

Inflammatory mediators released eg IL1, IFN-y Astrocyte activation (TGF-b) (inhibitors of inflammation), promotes glial scar formation

Question 50

What does angiogenesis do in a glial scar?

Answer 50

Forms new blood vessels in the tissues surrounding the damaged brain

Question 51

What are the benefits of a glial scar?

Answer 51

Maintenance of the BBB: - normally in scars, you get angiogenesis within the damaged tissue, allowing free movement of substances between the organ and the vasculature - with a gliosis scar, the damaged tissue in the middle is isolated from the surrounding angiogenesis proliferation, so the BBB is maintained, important for brains integrity

Question 52

What are the downsides of a glial scar?

Answer 52

Glial scar prevents neuronal regrowth via inhibition

Question 53

What are the consequences of stroke - depending on the region of brain affected (img pg352)

Answer 53

TACS - total anterior circulation syndrome PACS - partial anterior circulation syndrome LACS - lacunar syndrome POCS - posterior circulation syndrome

Question 54

What is a subarachnoid haemorrhage?

Answer 54

Haemorrhage into the subarachnoid space (rather than brain parenchyma as in typical haemorrhagic stroke). Has own specific risk factors different to haemorrhagic stroke.

Question 55

What are the causes of subarachnoid haemorrhage?

Answer 55

Saccular (berry) aneurysm Vascular malformation (in the subarachnoid region) Trauma

Question 56

What is a sacular (berry) aneurysm and how does it arise?

Answer 56

Abnormal dilatation of the wall of a blood vessel, arising due to defects in the media of blood vessels

Question 57

What is the presentation of a subarachnoid haemorrhage?

Answer 57

Sudden severe haemorrhage Loss of consciousness

Question 58

Summarise the different kinds of stroke

Answer 58

Read page 354 diagram!!!

Question 59

What is meningitis?

Answer 59

Inflammation of the meninges

Question 60

How does meningitis usually occur?

Answer 60

Usually due to an infection: Pathogen is able to exit the circulation, travel through endothelium and breach the BBB, so can access the subarachnoid space. Here it elicits an inflammatory response.

Question 61

What are the types of meningitis?

Answer 61

Acute bacterial mengitis Acute viral mengitis Chronic meningitis

Question 62

What are the routes of infection in bacterial meningitis?

Answer 62

Haematogenous spread from infection elsewhere - eg pharyngitis, otitis media, pneumonia Local infection eg sinusitis, spreads directly into subarachnoid space Direct implantation following trauma - exposure of CSF to external environment

Question 63

What is the pathogenesis of bacterial meningitis?

Answer 63

1. Colonisation of epithelial cells (eg respiratory) 2. Entry of pathogen into the bloodstream 3. Breach of blood brain barrier into subarachnoid space 4. Proliferation of pathogen in the subarachnoid space 5. Host inflammatory response

Question 64

What is the body’s inflammatory response to pathogens in the subarachnoid space?

Answer 64

Pathogen has PAMPs (foreign proteins) that the body recognises, and activates cells of the innate system like macrophages by binding to toll-like receptors These activate a series of intracellular signalling pathways, including the inflammasome complex, NLRP3, leading to the generation of pro-inflammatory cytokines such as IL1b and chemokines and complements, causing acute inflammation at the site. So chemotaxis and migration of neutrophils from blood into subarachnoid space. These neutrophils will degrade and phagocytose the pathogens in the subarachnoid space. Inflammation also causes damage and necrosis of host cells through release of its effector substances such as reactive oxygen species. The release of DAMPs from host cells elicits further inflammatory response from the innate immune system.

Question 65

After the release of DAMPs, what inflammatory response is caused?

Answer 65

Eg HMGB1 binding to the RAGE receptor, and DNA released from these necrotic cells activating toll-like receptors. All these will combine to cause further inflammation through release of inflammatory mediators.

Question 66

What are the complications of acute bacterial meningitis?

Answer 66

Cerebritis Ventriculitis Central abscess Raised ICP (numerous cells in subarachnoid space raises ICP) Death - eg by mechanisms of herniation and decreased conscious level

Question 67

What are cerebritis and ventriculitis?

Answer 67

When the infection and inflammation spreads from the meninges into the brain itself

Question 68

What is an abscess?

Answer 68

A collection of pus surrounded by fibrous tissue, forming a wall

Question 69

What are the causes of acute viral meningitis?

Answer 69

Enteroviruses Mumps Influenza Herpes simplex Varicella zoster …

Question 70

What is the pathogenesis of acute viral meningitis?

Answer 70

Similar pathogenesis to bacterial meningitis Main difference = chronic inflammation mediated by the adaptive immune system (as opposed to acute inflammation mediated by the innate immune system)

Question 71

What are the causes of chronic meningitis?

Answer 71

Tuberculous meningitis Fungal meningitis - eg Cryptococcus neoformans in immunocompromised individuals

Question 72

What is skin rash in meningitis associated with?

Answer 72

Meningococcal infection

Question 73

What are the characteristics of a meningococcal rash?

Answer 73

Macular (flat) and petechial (caused by minute bleeds in the skin) May become purpurin (small bruise in skin) Starts on legs and spreads rapidly (more difficult to identify on darker skin)

Question 74

What can a rash be indication of?

Answer 74

Rash can be indication of rapidly developing sepsis and urge for urgent antibiotics in these patients

Question 75

What is the pathogenesis of the meningococcal petechial rash?

Answer 75

1. Meningococcal septicaemia 2. Colonisation of endothelium of dermal blood vessels 3. Endothelial injury 4. Leakage of blood (from blood vessel) into peri vascular space (surrounding dermis) - can be seen on skin surface as petechia or purpura

Question 76

What’s the different between the rash seen in chronic meningitis vs viral meningitis?

Answer 76

Viral meningitis rash tends to be erythematous due to vasodilatation rather than petechial

Question 77

How can a glass test identify the type of rash?

Answer 77

A petechial rash will not blanch under pressure because erythrocytes have leaked into the perivascular space Erythematous rash will blanch because erythrocytes are intravascular and can therefore be squeezed away by pressure of the glass (so pressure of a non-blanching rash is concerning for a bacterial meningitis)