Neuropathology 1:trauma, infection, demyelination and neurogenerative diseases Flashcards
Epidemiology of head injury
How many visit A+E for it
How many are admitted to hospital?
How many are referred to neurosurgeons/ITU
How many die per year due to it?
Head injuries account or 30% to 50% traumatic deaths
What is the most common to the least common type of head injury?
1500/100,000 per year visits to A&E
300/100,000 per year admitted to hospital
15/100,000 per year referred to neurosurgeon/ITU
9/100,000 per year die
Head injuries account for 30% to 50% of all
traumatic deaths
Surface contusions, lacerations -95%
Diffuse axonal injury -90%
Skull fracture -75%
Cerebral oedema -75%
Intracranial haemorrhage -60%
Ischaemic brain damage -55%
Infection [abscess, meningitis] -4%
Males > females 3:1
Define the following 3 mechanism of injury to the brain
Define concussion, contusion and laceration
What symptoms do you get with a contusion?
What can you see wrong with the brains here?
Concussion - transient neurological dysfunction which is reversible - bit of amnesia and recover. Nothing seen on imaging.
Contusional injury - bruise to the brain(bleeding) - you get focal symptoms, contre-coup injury if the brain moves, common in frontal and temporal lobe, caused by burst lobe, intracerebral haemorrhage and post traumatic epilepsy
What damage occurs during a high velocity acceleration/deceleration with torsion.
What is this the a major cause of it?
What staining can be used to see there is this damage?
TAI = Axonal damage due to trauma
Diffuse axonal injury = most severe form of TAI
High velocity acceleration/deceleration with torsion - Major cause of post-traumatic Persistent Vegetative State (PSV)
Clinical effects immediate but cellular damage evolves over several hours
Axonal bulbs-24 hrs, beta APP in 2-3 hrs
Petechiae in corpus callosum, brainstem
3 grades of axonal injury: grade 1 - no macroscopic lesions grade 2 - haemorrhage in corpus callasum as well grade 3 - lesion in dorsolateral rostral brainstem as well
Gliding contusions: haemorrhage in parasagittal white matter, often bilateral but usually asymmetrical
What does this person have?
Diffuse axonal injury after 10 month survival post-injury
Traumatic vascular damage can happen due to?
Diffuse vascular damage – widespread petechial haemorrhages-death soon after injury 2) Damage to arteries in neck or intra-cranially causing infarction or focal ischaemia 3) Intracranial haemorrhage
What are the different causes of traumatic intracranial haemorrhage?
Extradural-arterial, sometimes no associated cerebral damage, lucid interval - admit and watch for 24 hours
B) Subdural-
- Acute, from damage to underlying brain or bridging veins
- Chronic, from bridging veins
- Risk factors; cerebral atrophy (age, dementia), coagulation dysfunction, anticoagulation therapy, alcoholism
C) Subarachnoid-damage to vertebral arteries in neck, or shearing of intracranial arteries
D) Intracerebral-often from contusions, may occur hours or even a day or two after injury (delayed intracranial haemorrhage)
What does this show?
Intraparenchymal haemorrhage/intracerebral haemorhage/contusion
What are secondary effects of head injury?
Ischaemia
1) Damaged brain more sensitive to hypoxia and hypercapnia/hypercarbia (CO2 retention)
2) Reduced circulation due toa-hypotension, hypovolaemia, for example surgical shock b-Raised Intra-Cranial Pressure (after failure of homeostasis in both instances)
3) Hypoxia may arise from a compromised airway or chest injuries
4) Infarction due to damage to an arterya-In intra-cranial compartment; b-Extracranially- carotid, vertebral arteries
Raised ICP
1) Cerebral oedema -Perfusion/circulatory problem -Reaction to haematoma -Direct reaction to rapid deceleration
2) Mass effect of haematoma
Infection
1) Meningitis
a-Compound depressed fracture of the skull b-Fracture of base of skull, through air sinusues, middle ear 2) Cerebral abscess- same routes
CHRONIC TRAUMATIC ENCEPHALOPATHY (CTE)
How does this happen?
How is it distinct from Alzheimer’s disease?
Neurodegenerative disorder in people with repetitive brain trauma eg contact sports (eg boxing, American football, rugby, ice hockey) or history of military service
In up to 30% of patients with h/o repetitive injury
Delayed onset with progression over time
Tauopathy(aggregation of tau protein into neurofibrallary or gliofibrillary tangles) seen , formerly known as ‘dementia pugilistica’, distinct from Alzheimer’s disease: mainly frontotemporal atrophy, but no beta-amyloid
Secondary effect of head trauma:
Post traumatic epilepsy:
When does it occur?
Whant type of injury is it more likely in?
What is the overall risk
Early(in first week/month)- Occurs in about 4-5% Late-40% start within 6 months, 50% <1 year. Early PTE gives 25% risk of late PTE.
Incidence relates to severity of injury-in the absence of intracranial haematoma, contusional damage, or depressed fracture, the risk of PTE is 1% (if you bled - higher chances of epilepsy)
Overall risk is 5%
Neurodegeneration is of 3 types:
Dementia only, Movement disorder, both dementia and movement disorder (give examples of each)
Why does neurodegeneration happen?
Why does protein misfolding occur?
How is endoplasmic reticulum dyfunction measured in experimental studies?
Dementia: Alzheimers
Movement: Parkinson’s
Movement and dementia: Huntingtons and diffuse lewy body
Protein aggregation is a common feature of neurodegenerative disease, and accumulations of intra- or extracellular insoluble fibrils form inclusions
Incorrect polypeptide folding resulting in an incorrect tertiary structure is the likely cause of catalytic enzyme resistance. It is these resistant molecules that form the inert fibrils
Prefibrillar intermediate forms (soluble oligomers and protofibrils) are also formed.
These intermediate forms cause toxicity, as demonstrated in Huntington’s disease. The insoluble deposits seem to be more inert generally
This misfolding of proteins is due to Endoplasmic reticulum dysfunction, which also plays a role in hypoxic damage.
Endoplasmic reticular stress (ER stress) is the process looked for evidence of the role of ERD in experimental studies.
Dementia
What is is the incidence in 70- 74, 75-80 , >90
What are the causes of dementia?
What are infectious causes of dementia?
What are common causes of dementia?
5% @ 70-74 yrs 20% @ 75-80 yrs 40% > 90 years - severe in 10%
Neurodegenerative disease Vascular disease (mostly atheroma, but there are others eg vasculitis, small vessel disease) Alcohol Hydrocephalus Metabolic-Hepatic & thyroid disease, B12 deficiency, Porphyria, Anaemia, Hypoxic Cerebral Tumours & paraneoplastic syndromes Autoimmune limbic encephalitis Chronic Traumatic Encephalopathy (Dementia Pugilistica) Multiple sclerosis
Infections Herpes Simplex Encephalitis HIV/AIDS Dementia complex Neurosyphilis Progressive Multifocal Leucoencephalopathy Subacute Sclerosing Pan Encephalitis
Common causes of dementia
Alzheimer’s disease 65-70% Vascular dementia 15-20% Lewy body dementia 10% Frontotemporal dementias 5% Others <1%
ALZHEIMER’S DISEASE
What happens to the brain?
What problems can you see under the microscope?
What are the risk factors
What factors reduce risk of getting alzheimers
Cerebral atrophy, mainly frontal and temporal; reduced dendritic branching
Neuritic plaques - NPs Neurofibrillary tangles - NFTs Amyloid angiopathy -AA Basal nuclei affected-loss of cholinergic input to cortex
Pathogenesis
Same features found in normal ageing to a lesser degree, (does AD represent wearing out of the brain?) Changes start earlier in life-American nun study NFT density correlates better to degree of dementia, but NFTs are found in other disorders NPs only found in AD, LBD and ageing Amyloid in NPs and AA is formed by beta amyloid protein, derived from Beta amyloid precursor protein BAPP (?primary event)
Neuritic plaques spread to the neocortex is pathomnemonic of alzheimers(grade 4,5,6 are alzheimers
Age Head injury Low educational status – but not socioeconomic status
FACTORS REDUCING RISK Cardioprotective lifestyle, statin therapy Active and socially integrated lifestyle Arthritis, inflammatory bowel disease
Alzheimers
What genetic factors increases risk for it?
Down’s syndrome- many have Alzheimer changes in 40s, develop dementia in 50s
Autosomal dominant forms-mutations in:
- BAPP gene, rare (Chromosome 21)
- Presenilin 1 gene-onset 30-50 yrs and is the commonest form -Presenilin 2 gene
Common factor is that they affect processing of BAPP
APOLIPOPROTEIN E4 -increase risk of dementia especially after head injury -> it also has high rate of MI, poor outcomes for head injury, bypass surgery and haemorrhage, greater psychological impairment after an event requiring rehab
E4 one allels = 3 x risk of AD. E4 homozygote = 8x risk compared to E3. Apolioprotein E -> involved in BAPP processing
BAPP is the normal protein which is broken down
Alpha secretase then beta secretase leads to aggregate alpha beta which is responsible for alzheimers disease
What therapy are available for alzheimer’s disease?
Anticholinegic agents-Arricept (Donezepil)- temporary partial reversal
- Immunization against amyloid b peptide-reduced plaques but no clinical improvement and induced encephalitic reaction in a few patients
- Clinical trials of Beta Secretase 1(BACE1) inhibitors are taking place
What does this person have?
Parkinson’s disease (-/+dementia, PDD) There is pigmented cell loss in the substantia nigra (with Lewy bodies in some remaining cells) leading to a loss of dopaminergic input to basal ganglia
Lewy body dementia / Dementia with Lewy bodies (DLB)
There are cortical Lewy bodies
90% also have Parkinsonism, and they often have visual hallucinations, a fluctuating course, and relative memory preservation
Lewy bodies contain a synuclein
Lewy body dementia you see lewy bodies in substantia nigra AND cortical neurone - movement disorder and dementia
What does this person happen
Where is the lesion commonly in
Volume of what matter is lost more
What are rare casuses of this
Multi-infarct dementia
Volume of grey matter lost
Lesions in dominant hemisphere
Lesions bilateral
Small vessel disease-associated with hypertensive changes-periventricular white matter damage
Rarer causes of small vessel disease include vasculitis and beta-amyloid angiitis
Fronto-temporal dementia
What are the different variants?
What are protein is affected and what genes and what chromosome number?
What are the pathological classifcation of this dementia?
Semantic-variant primary progressive aphasia - a disorder of semantic knowledge and naming
- Non-fluent variant primary progressive aphasia with language deficits
- Behavioural variant- Initial relative preservation of memory with deterioration in personality and behaviour, disinhibition, lack of insight, inflexibility, stereotypic behaviour, and late onset alcoholism may occur
Over 5% of dementias-often only diagnosed at autopsy • 30-50% cases are familial-50% of these have mutations of tau (on chromosome 17) or progranulin genes. Linkeage to Chromosome 9p 21.2-31.3 in MND cases
Pathological classification
Pick’s disease-Pick bodies that are tau positive (one of the tauopathy disorders) - rare but massive degeneration seen
• Ubiquitin positive proteinopathies- includes dementia in Motor Neuron Disease and MNDtype inclusions. Many have TDP 43, a small number have FUS (fused in sarcoma) • Frontotemporal degeneration with no specific histology
What does this person have?
Caudate nucleus are flat and in late stage become concave
HUNTINGTON’S DISEASE
Progressive dementia and choreiform movement - onset in adulthood
Prion disorder
Name 3 different types of disease caused by prions
What is the pathology behind them?
When should you suspect prion protein disease?
What are prion properties?
Kuru
Creutzfeldt-Jakob disease -sporadic -iatrogenic -variant
Fatal familial insomnia
Pathology
Spongiform change, neuronal loss, gliosis Amyloid plaques in some cases, mostly in the cerebellum There are numerous amyloid plaques in the cerebellum and also the cerebral cortex in variant CJD (vCJD), with spongiform change around them
PRION -proteinaceous infective particle
Normal prion protein is part of the cell membrane (PrP)
Abnormal, protease resistant form is agent causing TSEs (PrPsc)
cooperative converstion - normal prion can turn to abnormal ones - 6 months = dementia
Prion properties
PrPsc induces cells to switch from PrPn to PrPsc production May form amyloid Highly resistant to “sterilization” There are familial TSEs. All of them have a mutation of the prion gene
What does this person have?
What sort of pathology is it?
What sort of problems can it cause?
What is the mean age and which gender gets it more?
Multiple sclerosis
Relapsing/remitting neurological condition with gradual accumulation of neurological deficit
Sequential development of multiple lesions with demyelination-relative axonal sparing, inflammation, gliosis
Affects in particular the optic nerves, periventricular white matter, cerebellum, brainstem and spinal cord.
May cause a variety of problems including optic neuritis, spinal cord syndrome, ataxia, depression, cognitive problems
Loss of myelin sheaths with relative axonal preservation
– T cell mediated immune response to myelin antigens? (cf experimental allergic encephalomyelitis)
– Now thought that oligodendrocyte apoptosis may be the primary event
Epidemiology
Mean age of onset 30 yrs Male:female 1:1.5 Prognosis-from death within months to asymptomatic survival until death from other cause Little disability in 30% for 15 yrs (benign MS), and 25 yrs for 10% Overall reduction of life expectancy of a few years.
More common in the the North than the south
There may be effects of sun, migration and ethnic origin - rare in far east. Concordance in 30% monozygotic twins and 2% in dizygotic twins
