Week 3 - G - Neuropathology 2 - CNS demylination and dementia

Question 1

What do oligodendrocytes form to precipitate rapid slatatory conudction?

Answer 1

They form nodes of ranvier which greatly increase the speed of nerve impulse conduction

Question 2

Do oligodendrocytes or schwann cells have a limited capacity to remyelinate after damage? Think about which is CNS and which is PNS

Answer 2

Oligodendrocytes have a limited capacity to remyelinate themselves after damage - this is the CNS Schwann cells have a greater remyelination capability - PNS

Question 3

Demyelinating disorders can be classified as primary or secondary What is the main primary cause of demyelination? What is a primary cause that is rare and usually occurs in children, after a viral infection? symptoms can resemble the main primary cause

Answer 3

Main primary cause - Multiple sclerosis Acute disseminated encephalomyelitis - self limiting

Question 4

Why does acute disseminated encaphlomyelitis occur?

Answer 4

Can typically occur after a minor infection such as a cold- the immune system becomes mis-programmed and activates immune cells to talk the healthy myelin covering the nerves

Question 5

Acute disseminated encephalomyelitis is most commonly self limiting, what is the fatal form of ADEM where there is usually bleeding as it is a necrotizing vasculitis?

Answer 5

Acute haemorrhagic leukoencephalitis

Question 6

Secondary demyelination can occur due to viral infection, such as JC virus This viral infection is seen as a side effect of certain MS treating drugs What can JC virus cause?

Answer 6

Progressive multifocal leukoencephalopathy (PML) is a rare (in the general population) but serious demyelinating disease of the brain, often resulting in severe disability or death, caused by lytic infection of oligodendrocytes by the JC polyomavirus (JCV).

Question 7

When there is over-rapid therapeutic correction of hyponatraemia, triggering oligodendrocyte death… …demyelination can occur as a result. What is this ocndition known as? Is this primary or secondary demyelination?

Answer 7

Secondary demyelination due to rapid correction of hyponatraemia - known as central potine myelinosis

Question 8

When is the peak incidence of multiple sclerosis and in which gender is it more common?

Answer 8

Peak incidence is 20-30years old, more common in females

Question 9

What does mutiple sclerosis have a correlation with?

Answer 9

There is a well known correlation with latitude in that less sunlight means less vitamin D and therefore more northern countries have an increased rate of people with MS

Question 10

Define multiple sclerosis

Answer 10

Autoimmune demyelinating disordr characterised by distinct episodes of neurological defecits, distinct in time and distinct neurological defects implicating two different sites of foci

Question 11

What is needed for a diagnosis of MS?

Answer 11

Two distinct neurological deficits occurring at distinct times A neurological defecit implicating one neuro-anatomical site and an MRI scan appreciated defect at another neuro-anatomical site Mutliple dinstinct (usually white matter) lesions in the CNS

Question 12

What can be seen on a lumbar puncture when checking for MS?

Answer 12

IgG Oligoclonal bands in the CSF

Question 13

MS typically presents with the emergence of a focal neurological deficit What are the visual related neurological deficits that can occur in MS? - describe the sypmtom Is it usually unilateral or bilateral?

Answer 13

Unilateral (usually) optic neuritis - this is when there is pain on movmeent of the eye and a decrease in central vision (known as a central scotoma) INternuclear ophthalmopegia - usually bilateral in young patients with MS - if there is a lesion in the right medial longitdunial fasciculus (MLF) - the ipsilateral right eye will fail to adduct and the contralteral left eye will have nystagmus on abductio

Question 14

There is a long list of clincial features of MS Name the optic nerve lesion problem? Spinal cord lesion problems? Brain stem lesions?

Answer 14

Optic nerve lesion - optic neuritis Spinal cord lesions - bladder dysfunction, spascticity, motor or sensory deficit in the limbs Brainstem lesiosn - ataxia, nystagmus, internuclear ophthalmoplegia

Question 15

What are the different motor and snesory tracts in the spinal cord? Would a spinal cord lesion in these tracts cause contralateral or ipsilateral deficit What sensations do these tracts provide?

Answer 15

Dorsal column medial lemniscus tract - fine touch, vibration and proprioception - decussates in the medulla so ipsilateral if spinal cord lesion Spinothalamic tract - crude touch, pain and temperature - decussate in spinal cord (usualy about 2 levels above the dermatome level) - contralteral deficit if spinal cord lesion Corticospinal tract (pyramidal) - motor supply and decussate at medullary level so ipsilateral if spinal cord lesion

Question 16

What are the different types of MS?

Answer 16

Relapsing remitting MS - 8out10 patients so most common Primary progressive MS - second most common Secondary progressive MS Progressive relapsing MS

Question 17

Describe the different types of MS? Around half of the patinets with relapsing remitting MS will develop secondary progressive MS in how long? What is the most debilitating form of MS?

Answer 17

Relapsing remitting - around half of the patients with this will go on to develop secondary progressive MS within 15-20 years Progressive relapsing is the most debilitating form as patients will have a steady decline with superimposed MS attacks

Question 18

What scan is used to aid in the diagnosis of MS? What is needed for diagnosis of MS remember?

Answer 18

MRI scan can be used Lesions disseminated in time and space - distinct focal neurological deficit implicating different neuroanatomical sites and distinct in time Can see the plaques on this T2 weighted scan

Question 19

Is MS typically a white matter or grey matter disease and why?

Answer 19

Typically a white matter disease as this is where the axons from cell bodies (found in grey matter) are located hence the demyelination will occur where the myelin is

Question 20

Are the shapes well demarcated or not?

Answer 20

he plaques are usually well demarcated

Question 21

The plaques Can occur at any site in the CNS Lesions tend to be distributed in a non-symmetrical and non-anatomical manner. Where are the plaques often seen?

Answer 21

Often seen in Cranial nerve 2 - optic nerve Corpus callosum Cerebellum Brainstem (where the MLF - medial longitudinal fasciculus is found) Spinal cord lesions

Question 22

In MS you can get acute (active) plaques and inactive (chronic) plaques Active plaques occur whilst demyleination is happening and inactive plaques are seen once the demylination has occured Describe what is seen histologically in the acute and inactive stage?

Answer 22

Acute plaques - ongoing demyleination, perivascular inflammation (12-24 hours you see red neurons, 24-48hours you see neutrophils, 48hours on theres is microglia) Inactive plaques - evidence of scarring and gliosis histologically is seen (after about a week of cell damage)

Question 23

Environmental factors in multiple sclerosis Association with latitude Relationship with Vitamin D deficiency. Sunlight exposure What is the genetic factor haplotype linked to multiple sclerosis?

Answer 23

It is linked to the HLA DRB1 gene

Question 24

Is multiple sclerosis multifactorial, genetic or environmental?

Answer 24

Multiple sclerosis is an autoimmune disease of multifactorial etiology The etiology of multiple sclerosis is linked to a variety of genetic and environmental factors.

Question 25

Name two neurodegenerative diseases affecting the basal ganglia? Name a huge neurodgenerative broad category affecting the cerebral cortex?

Answer 25

Basal ganglia - Parkinson’s disease and Huntington’s disease Cerebral cortex - dememnita

Question 26

Dementias are also characterised by progressive loss of neurons, typically affecting functionally related neuronal groups And often show symmetrical involvement of neurones, which contrasts with multiple sclerosis. Is dementia part of the normal ageing process?

Answer 26

Dementia is never part of the normal ageing process - it is always pathological

Question 27

What are the four main primary types of dementia?

Answer 27

Alzheimer’s disease Lewy-body dementia Pick’s disease (fronto-temporal dementia) Huntington’s disease

Question 28

What is the important type of secondary dementia?

Answer 28

This would be vascular dementia (multi-infarct dementia)

Question 29

What is the most common type of dementia and what % of cases does it account for? What is the second and third most common causes of dmeentia?

Answer 29

Most common type - Alzheimer’s disease - 60-75% of cases Second most common - Vascular dementia Third most common - Lewy body dementia Fronto-temporal dementia is the fourth most common cause

Question 30

Most common cause of dementia in elderly is Alzheimer’s disease When does the age of onset of Alzheimer’s usually occur?

Answer 30

Usually occurs after 60 years of age but early onset can be younger

Question 31

Alzheimer’s disease has the potential to be familial What preotins have an asccoiated mutation in patients with Alzhiemer’s disease hence the familial aspect in a small number of cases ? What condition is there an increase in the incidence of AD?

Answer 31

Amyloid beta precursor protein - gene for this protein is found in chromsome 21 Or in the presenilin 1 (chromosome 14) and 2 proteins (chromosome 1) In Down’s syndrome, there is an increased incididence of AD, perhaps becuae there are now 3 chromosome 21 genes where the amyloid beta precusor protein is located and hence a higher chance of mutation

Question 32

AD Becomes clinically apparent as an insidious impairment of higher intellectual function, with alterations in mood and behaviour. The onset can often be subtle, but once symptoms and signs are established, there is a steady progression What are some syptoms of more progressive AD?

Answer 32

Progressive disorientation Memory loss Aphasia (trouble with word finding)

Question 33

While some atrophy does occur in ageing, the degree of atrophy in Alzheimer’s disease is far more marked… …underlying the fact that Alzheimer’s is a disease and not merely a more accelerated aspect of the ageing process What can happen macroscopically to the brain?

Answer 33

There is increased cortical atrophy resulting in the widening of the sulci in the brain and narrowing of the gyri

Question 34

a term used to describe the increase in the volume of CSF, characterised on images as an enlargement of cerebral ventricles and subarachnoid spaces, caused by encephalic volume loss. What is this known as? It is seen when the ventricles enlarge in AD as well as other encephalic volume loss causing disease

Answer 34

This is known as hydrocephalus ex vacuo - compensatory enlargement of the CSF spaces often seen as a part of the ageing process but also seen pathologically

Question 35

Which lobe of the brain is spared in Alzheimer’s disease?

Answer 35

Occipital lobe is spared

Question 36

What are the microscopic pathological features seen in Alzheimer’s disease?

Answer 36

Loss of cortical neurones - Extensive neuronal loss with associated astrocyte proliferation - Simple neuronal atrophy - Gliosis Neurofibrillary tangles - Tau protein aggregates Neuritc plaques due to amyloid beta protein

Question 37

Cerebral amyloid angiopathy also contributes to the amount of amyloid causing toxicity in the brain increasing the risk of Alzheimer’s disease How is amyloid angiopathy stained?

Answer 37

Use congo red staining and see a positive apple-green birefringence

Question 38

What medication is given in the treatment of Alheimer’s disease?

Answer 38

Anticholineesterase inhibitors (AChE inhibitors) eg donepezil, rivastigmine, glantamine)

Question 39

Acetylcholinesterase inhibitors are given in the treatment of mild to moderate dementia WHen the dementia progresses and the treatment stops working as well, what drug type can be tried?

Answer 39

NMDA receptor antagonists e.g. memantine used in moderate to severe In Alzheimer’s disease, excess glutamate can be released from damaged cells, leading to chronic overexposure to calcium, which can speed up cell damage. Memantine helps prevent this destructive chain of events by partially blocking the NMDA receptors that glutamate binds to (memantine is an anti-glutaminergic treatment). - NMDA-glutamate receptors allow for influx of CALCIUM, sodium and efflux of potassium

Question 40

What is the drug treatment that can be given as a herbal remedy to treat Alzheimer’s dementia?

Answer 40

Ginkgo biloba - herbal remedy - interacts with warfarin

Question 41

How does lewy body dementia typically present? How common is it?

Answer 41

Lewy body dementia is he third most common type of dementia - roughly 10% Presents with progressive dementia, along with hallucinations and fluctuating levels of attention/cognition

Question 42

There is some overlap with Alzheimer’s and Lewy body dementia, which type typically affects memory later on? Fluctuation in severity of condition on a day-to-day basis What other disease features is there an association with in Lewy Body dementia that is important for diagnosis?

Answer 42

Lewy body dementia typically affects memory later in the course of the disease than Alzheimer’s disease There is the association with motor features of Parkinsonism, which are typically present at diagnosis, or emerge soon after

Question 43

What are the clinically parkinsonism features of Lewy body dementia?

Answer 43

Loss of facial expression (hypomimia) Stooping and shuffling gait Rigidity - slow to intiate mvoement Bradykinesia Pill rolling resting tremor

Question 44

All people with Lewy body dementia will go on to get parkinsonism What percentage of those with Parkinson’s disease will go on to get Lewy body dementia by 20 years? What causes Parkinson’s disease?

Answer 44

80% of patients after having Parkinson’s disease for at least 20 years will have gone on to have Lewy Body dementia Parkinson’s is caused by the degeneration of the dopaminergic neurons in the substantia nigra (pars compact)

Question 45

What is seen macroscopically in Lewy body dementia?

Answer 45

Pallor in the substantia nigra where it usually black showing the absence of the dopaminergic neurons Substanita nigra is located in the midbrain

Question 46

In a patient with Lewy body dementia, or Parkinson’s, what is the protein known as that forms the Lewy bodies and Lewy nitrites?

Answer 46

This is the alpha synuclein protein

Question 47

What age does Huntington’s disease present in each gender? What is the mode of inheritance? What is the genetic mutation causing Huntingotn’s disease? Does Huntington’s disease cause a primary or secondary demenita?

Answer 47

Huntingtons disease presents in the 4th decade in women and 6th decade in men (30s and 50s) Autosomal dominant - cause by a triple nucleotide expansion , causing a CAG triplet repeat in the Huntingtin gene on chromsome 4, greater than 35 repeats causes the features of Huntingtin’s Huntingtin’s caused primary dementia

Question 48

Clinical features: triad of emotional, cognitive and motor disturbance is seen in Huntington’s disease What are some of the symptoms?

Answer 48

Irritability, depression Chorea (dance like movements), slurred speech , apathy

Question 49

What is usually the treatment options for Huntington’s disease? Which part of the basal ganglia is usually affected in Huntingotn’s disease?

Answer 49

Usually anti-depressants and exercise is proven to help in Huntington’s disease Typically the sriatum (caudate nucleus + putamen) (corpus striatum = caudate nucleus +putamen + globus pallidus)

Question 50

Cortical atrophy occurs later in Huntington’s disease What is the compensatory mechanism seen in the lateral ventricles known as here?

Answer 50

Hydrocephalus ex vacuo

Question 51

What is another name for fronto-temporal dementia? What age group does this dementia usually occur?

Answer 51

Pick’s disease Usually occurs between the ages of 50-60 years

Question 52

Fronto-temporal dementia has the atrophy as seen in Alzheimer without the AD histology What are some of the symptoms of FTD ? What loves are spared from atrophy?

Answer 52

Pathologically there is extreme atrophy of the frontal and temporal lobes, with sparing of parietal and occipital lobes. Symptoms Characterised by progressive changes in behaviour, personality and social deterioration, leading to impairment of intellect, memory and language.

Question 53

Is personality changes due to frontal or temporal lobe atrophy? Is language problems due to frontal or temporal lobe atrophy?

Answer 53

Personality hanges due to frontal atrophy Language problems due to temporal atrophy

Question 54

What is seen histologically in Pick’s disease?

Answer 54

Pick’s proteins enriched with Tau potein are seen histologically Tau protein thereforre seen in both Fronto-temporal and Alzheimers dementia

Question 55

Disorder involving a deterioration in mental functioning due to cumulative damage to the brain through hypoxia or anoxia (lack of oxygen) as a result of multiple blood clots within the blood vessels supplying the brain. What is this?

Answer 55

This is multi-infarct dementia (Vascular dementia)

Question 56

Successive, multiple cerebral infarctions cause increasingly larger areas of cell death and damage. When a sufficient area of the brain is damaged, dementia results. What gender is it more common in? Where does this rank in the causes of dementia?

Answer 56

More common between men than in women And this ranks as the second most common form of dementia

Question 57

Difficult to distinguish from Alzheimer’s disease, however there are clues to help What is the difference in disease onset and disease progression?

Answer 57

Alzheimers has an insidious gradual onset with a steadily progressing deterioration

Vascular dementia has an abrupt onset with a stepwise progression - reflecting the stepwise deterioration due to episodic vascular induced brain infarction

Question 58

What is there likely to be a history of in a patient with vascular dementia?

Answer 58

History of hypertension, TIAs and/or stroke

Question 59

Is it more common to have large vessel or small vessel infarcts in Multi-infarct dementia?

Answer 59

It is more common to have large vessel infarcts eg te cerebral arteries than small vessel eg lacunar (lenticulostriatal) artery infarcts in MID