W7 33 neuropathology Flashcards
How does raised intracranial pressure occur?
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.
What are some causes of raised intracranial pressure?
Head injury/haemorrhage
Infection
Neoplasia
Hydrocephalus
Cerebral oedema
What is hydrocephalus?
Obstruction to the flow of CSF, leading to compression of brain and expansion of ventricles
What is cerebral oedema and how does it occur?
Accumulation of fluid in the brain, a response to either:
- vasogenic injury (causing increased vascular permeability)
- cytotoxic damage (injury to neuron/glial membranes)
What are the effects of raised intracranial pressure?
Headache, vomiting, seizures
Reduced conscious level
Papilloedema (changes in retina)
Herniation
What is herniation?
Protrusion of one part of the brain into another compartment
What are the 3 types of herniation and where are their sites of lesion? (IMG PP341)
Subfalcine (cingulate) - frontal lobe
Transtentorial (uncinate) - lateral supratentorial
Tonsillar - posterior fossa
Which herniation cause significant clinical problems?
Transtentorial and tonsillar herniations can cause significant clinical problems
Subfalcine herniation doesn’t usually cause symptoms
Why does subfalcine herniation not usually cause clinical problems and what is the exception to this?
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
What are the effects of transtentorial herniation?
Compression of third cranial nerve
Compression of posterior cerebral artery
Compression of contralateral cerebral peduncle
Tearing of vessels in upper brainstem
Transtentorial hernation can cause compression of the third cranial nerve. What can this lead to?
Ipsilateral pupillary dilatation
Ophthalmoplegia
Transtentorial hernation can cause compression of the posterior cerebral artery. What can this lead to?
Ischaemia to visual cortex, so visual disturbance
Transtentorial hernation can cause compression of the contralateral cerebral peduncle. What can this lead to?
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)
Transtentorial hernation can cause tearing of vessels in the upper brainstem. What can this lead to?
Due to mechanical effects of herniation through the small aperture
Duret haemorrhage
What are the effects of tonsillar herniation?
(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
What are the types of traumatic brain injury?
Parenchymal tissue damage
Vascular tissue damage
What can parenchymal tissue damage cause?
Concussion
Contusions
Diffuse axonal injury
What can vascular tissue damage cause?
Epidural haematoma
Subdural haematoma
Subarachnoid haemorrhage
Intraparenchymal haemorrhage
What is a concussion?
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
What is contusion?
Contusion = bruising. Results in pathological appearance of brain.
What is coup contusion and contrecoup contusion?
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
What is diffuse axonal injury?
Form of acceleration/deceleration injury eg in RTA, leading to widespread tearing of axons
What is epidural haematoma?
Accumulation of arterial blood between inner skull surface and dura
What is the pathogenesis of an epidural haematoma?
Usually due to skull fracture damaging artery in dura
The middle meningeal artery is particularly susceptible
What is the presentation of an epidural haematoma? (IMG PG345)
Lucid interval for several hours followed by progressive neurological impairment
What is a subdural haematoma? (IMG PG345)
Accumulation of venous blood between the dura and outer surface of the arachnoid membrane
What is the pathogenesis of subdural haematoma?
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)
What is the presentation of subdural haematoma?
Focal neurological signs
Personality change, confusion etc (non specific)
What is a stroke?
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.
What are signs of focal disturbance of cerebral function called if they last less than 24 hours?
Less than 24hrs are transient ischaemic attacks - TIAs
Are ischaemic or haemorrhagic strokes more common? (Image of each pg346)
Ischaemia (85%) are more common than haemorrhagic (15%)
What are the causes and risk factors of these causes for ischaemic stroke?
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
What happens when cerebral perfusion falls?
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.
What is the haemostatic response to falling perfusion (past certain point)? (PG347 IMG)
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.
What happens if the blockage is removed?
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.
What are the mechanisms of neuronal ischaemia? (PG348 LOOK AT IMG!)
- Thromboembolism causes neuronal ATP depletion - reduced oxygen and glucose delivery to cells results in anaerobic metabolism with less ATP production
- 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. - 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.
What is an MCA infarct?
Thrombus in the middle cerebral artery
What is the morphology of acute ischaemic stroke? (Pg348 img)
Dusky discolouration of affected grey matter
Blurring of cortical margins
Swelling with midline shift
What is a haemorrhagic transformation of ischaemic stroke?
Secondary haemorrhage into a bland ischaemic infarct (pre-existing ischaemic stroke)
What is the pathogenesis of haemorrhagic stroke?
Happens due to ischaemic damage to vascular endothelium, blood leaks out causing haemorrhage.
What are the risk factors for haemorrhagic stroke?
Large infarct
Antithrombotic medication eg warfarin
Thrombolytic drugs
What are causes of haemorrhagic stroke?
Hypertension
Cerebral amyloid angiopathy
How does hypertension cause haemorrhagic stroke?
Causes a rupture of small intraparenchymal blood vessels
Typically affects basal ganglia, thalamus, pons and cerebellum (brainstem and lower parts of brain)
How does cerebral amyloid angiopathy cause haemorrhagic stroke?
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
What considerations are there for inflammation and healing following stroke?
Neurones are permanent cells
Scarring is mediated by gliosis rather than fibrosis
What occurs at different time frames for inflammation and healing following a stroke?
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
What are the components of the glial scar?
Astrocytes
Cytokines secretion by microglia
Angiogenesis
What do astrocytes do in the glial scar?
Hypertrophy and hyperplasia with formation of numerous branching cell processes.
They secrete extracellular matrix proteins.
What does cytokine secretion by microglia do in a glial scar?
Inflammatory mediators released eg IL1, IFN-y
Astrocyte activation (TGF-b) (inhibitors of inflammation), promotes glial scar formation
What does angiogenesis do in a glial scar?
Forms new blood vessels in the tissues surrounding the damaged brain
What are the benefits of a glial scar?
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
What are the downsides of a glial scar?
Glial scar prevents neuronal regrowth via inhibition
What are the consequences of stroke - depending on the region of brain affected (img pg352)
TACS - total anterior circulation syndrome
PACS - partial anterior circulation syndrome
LACS - lacunar syndrome
POCS - posterior circulation syndrome
What is a subarachnoid haemorrhage?
Haemorrhage into the subarachnoid space (rather than brain parenchyma as in typical haemorrhagic stroke). Has own specific risk factors different to haemorrhagic stroke.
What are the causes of subarachnoid haemorrhage?
Saccular (berry) aneurysm
Vascular malformation (in the subarachnoid region)
Trauma
What is a sacular (berry) aneurysm and how does it arise?
Abnormal dilatation of the wall of a blood vessel, arising due to defects in the media of blood vessels
What is the presentation of a subarachnoid haemorrhage?
Sudden severe haemorrhage
Loss of consciousness
Summarise the different kinds of stroke
Read page 354 diagram!!!
What is meningitis?
Inflammation of the meninges
How does meningitis usually occur?
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.
What are the types of meningitis?
Acute bacterial mengitis
Acute viral mengitis
Chronic meningitis
What are the routes of infection in bacterial meningitis?
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
What is the pathogenesis of bacterial meningitis?
- Colonisation of epithelial cells (eg respiratory)
- Entry of pathogen into the bloodstream
- Breach of blood brain barrier into subarachnoid space
- Proliferation of pathogen in the subarachnoid space
- Host inflammatory response
What is the body’s inflammatory response to pathogens in the subarachnoid space?
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.
After the release of DAMPs, what inflammatory response is caused?
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.
What are the complications of acute bacterial meningitis?
Cerebritis
Ventriculitis
Central abscess
Raised ICP (numerous cells in subarachnoid space raises ICP)
Death - eg by mechanisms of herniation and decreased conscious level
What are cerebritis and ventriculitis?
When the infection and inflammation spreads from the meninges into the brain itself
What is an abscess?
A collection of pus surrounded by fibrous tissue, forming a wall
What are the causes of acute viral meningitis?
Enteroviruses
Mumps
Influenza
Herpes simplex
Varicella zoster …
What is the pathogenesis of acute viral meningitis?
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)
What are the causes of chronic meningitis?
Tuberculous meningitis
Fungal meningitis - eg Cryptococcus neoformans in immunocompromised individuals
What is skin rash in meningitis associated with?
Meningococcal infection
What are the characteristics of a meningococcal rash?
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)
What can a rash be indication of?
Rash can be indication of rapidly developing sepsis and urge for urgent antibiotics in these patients
What is the pathogenesis of the meningococcal petechial rash?
- Meningococcal septicaemia
- Colonisation of endothelium of dermal blood vessels
- Endothelial injury
- Leakage of blood (from blood vessel) into peri vascular space (surrounding dermis) - can be seen on skin surface as petechia or purpura
What’s the different between the rash seen in chronic meningitis vs viral meningitis?
Viral meningitis rash tends to be erythematous due to vasodilatation rather than petechial
How can a glass test identify the type of rash?
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)
