Pathology and Disease of the CNS

Question 1

Outline the global epidemiological status of epilepsy

Answer 1

Epilepsy is the most common serious chronic neurological condition

Lifetime epilesy prevalence is 2-4%

(Note: lifetime prevalance of seizures unrelated to epilepsy = 9%)

The prevalence of epilepsy is increased in underdeveloped contries and lower socioecononmic groups (largely due to increased rates of brain diseases)

Question 2

What is **sudden unexplained death in epilepsy **(SUNDEP)?

Answer 2

SUNDEP is the most common cause of death in epileptic patients

There is no known mechanism of how death occurs in this sydrome.

• Overall incidence in epilepsy = 5/10,000
• Medical refractory patients = 2-5/1000
• Surgical candidates/pailures = 10-15/1000

Other known causes of mortality of epileptic patients include accidental injury, drowning asphyxia, status epilepticus and suicide.

Question 3

What is an epileptic seizure?

Answer 3

A transient occurance of clinical signs and/or symptoms due to excessive and hyper-synchronous activity of populations within the brain that disrupts nerological processing.

Every patients seizure is different but there are basic patterns of seizure that people tend to follow.

Having a seizure does not mean a person has epilepsy - seizures can occur as the result of trauma, strokes etc.

Question 4

What are the three ILAE classifications of seizures?

Answer 4

Partial Seizures

Arise in a limited number of cortical neurons within one hemisphere. Tend to result from focal structural abnormalities to the brain area.

Generalised Structure

Appear to arise simultaneously in both hemispheres. Tend to result from genetic epilepsy.

Unclassifable Seizures

Unable to be determined / categorised

Question 5

What does ILAE stand for

Answer 5

The ILAE stands for International League against Epilepsy

They develop and maintain classifiations of seizure and epilepsy conditions

Question 6

What are the three ILAE classications of epilepsy and epileptic syndromes?

Answer 6

Genetic (Idiopathic)

Underlying brain is structurally and functionally normal; but complex polygenetic variations (probably ion channels) causes induces epileptic changes to neuronal circuitry

• Onset is generally in childhood/adolescence
• Generally respond well to treatment (important to ensure complience in demographic)
• Genetic basis - probably ion channel changes

Structural/Metabolic (symptomatic)

Seizures result from some identifiable structural/functional brain abnormality

• Onset generally in older people
• Uncommonly remit ( remit = to become less severe with time)
• Unable to be fully controlled with medication

_Unknown _

Question 7

Diagnosing the type of epilepsy a patient has is important for what considerations?

Answer 7

Prognosis

• Response to treatment
• Likelihood of remission
• Development of other neurological features

Treatment Options

• Medical treatment
• Surgical treatment (needs to be circumscribed to a focal area that is excisable)

Genetic Counselling/Implications

Question 8

What causes epilepsy?

Answer 8

Epilepsy results from a disturbance in the balance between the excitation and inhibition of cortical neurons or neuronal networks that results in networks that fire in an uncontrolled, hypersynchronous and self sustaining manner

Question 9

What is medial medullary syndrome?

Answer 9

Medial medullary syndrome is the result of a cerebrovascular incident associated with the anterior spinal artery.

Ischemia and infarction of the vascular territory supplied by the anterior spinal artery - the medial medulla - leads to recognisable neurological deficits.

It impacts:

1. Hypoglossal nucleus

Ipsilateral paralysis and atrophy of tongue (LMN) - deviation of tongue occurs towards the side of the lesion

2. Medial Lemniscus

Contralateral somatosensory deficit

3.** Pyramids**

Contralateral hemiparesis (UMN)

Question 10

List the common types of injuries that occur to strucutres of the head as a result of trauma.

Answer 10

Scalp = laceration (scalp is highly vascular - profuse bleeding)

Skull = fractures

Meninges = vascular injury and laceration

Brain/spinal cord = contusions, lacerations, diffuse axonal injury (DAI), diffuse vascular injury

Question 11

What is meant by the term concussion?

Answer 11

Concussion is a clinical term that describes the syndrome of:

• instantaneous loss of conciousness
• temporary respiratory arrest, and
• loss of reflexes

It occurs following sudden change in the momentum of the head - the brain moves around inside and incurs injury as a result of impact.

Pathogenesis is uncertain but is though to involve the reticular activating system of the brainstem.

Question 12

Describe the epidemiology of traumatic brain injuries (TBI)

Answer 12

Central nervous system injuries are the leading cause of death in people <45 y.o in Western countries.

Overall:

• 1% of all deaths
• 30% of deaths from trauma
• 50% of deaths from motor vehicle accidents

Most importantly: is a major cause of severe and chronic disability as a result of neurological dysfunction

Question 13

Briefly list the common secondary effects of TBI’s

Answer 13

Acute phase of injury:

1. Ischemia

2. Hypoxia

Delayed phase of injury:

3. Cerebral swelling (elevated ICP)

4. Infection

5. Epilepsy

Question 14

Describe the terminology and consequences of skull fractures

Answer 14

Skull fractures are important to diagnose because they are an indicator of a high energy transfer injury

Skull fractures tend to radiate from the point of impact. Fractured skull bone may also be depressed - sitting in the meninges of the brain with no structural integrity.

If the fractured skull communicates to the surface of the skin, it is an **“open” fracture. **If not communicating to scalp surface it is a “closed” fracture.

“Comminuted” fractures occur where splintering of the bone into small, sharp pieces has occured due to high energy transfer.

The leakage of blood of CSF from the nose and/or ears may result from basal skull fractures.

Question 15

Characterise an extradural haematoma

Answer 15

Extradural haemorrhage:

• Typically due to a blow to the **pterion **and tearing of middle meningeal artery
• Blood accumulates rapidly over minutes to hours due to high pressure arterial haemorrhaging
• Classic time course: head injury - brief period of unconsciousness - improvement - rapid deterioration
• Less common in older people: with age the dura mater becomes more adhesive to the skull and the epidural space is shruken/lost.

Question 16

Characterise a subdural haemorrhage

Answer 16

Results from the rupture of superior cerebral veins at the site where they enter the dural venous sinus.

• Leads to accumulation of blood in subdural space.
• Usually follows an injury (sometimes minor), can also be caused by other mechanical disturbances such as shaken-baby syndrome
• Common in the elderly as they have shrunken brain which places extra stress on the cerebral veins entering the dura.
• Can occur spontaneously if on anticoagulants
• Symptoms can be similar to dementia and may not appear for days, weeks or months; are indolent (little pain) and may fluctuate

Question 17

Describe the terminology and pathology relating to **contusions **

Answer 17

Contusions are brain injuries caused by the transmission of kinetic energy to the brain parenchyma.

Blows to the surface of the brain, transmitted through the skull, leads to rapid tissue displacement, disruption of vascular channels, and subsequent hemorrhage, tissue injury, and **edema **

Ultimately results in haemorrhaging necrosis (bruising)

Coup = contusion at impact site

Contrecoup = contusion involving opposite side of the brain to impact when the head is not immobilised at time of injury

Contusions are most common to basal/inferior regions of the brain: **inferior frontal and temporal lobes. **Contusions to these regions often result in deficits to the olfactory bulb (leading to anosmia)

Question 18

Characterise subarachnoid haemorrhages

Answer 18

Subarachnoid haemorrhages are the spontaneous rupture of sacular “berry” aneurysms within the circle of Willis

• Dramatic onset of thunderclap headache (“worst headache of my life”), often in occipital region
• Closely followed by vomiting and often coma and death if untreated

Question 19

Characterise

Answer 19

Intra-cerebral haemorrhages can occur as a result of:

1. Cortical lacerations associated with depressed skull fractures
2. Degeneration of small deep penetrating arteries (often due to chronic hypertension associated hyaline _**_arteriolosclerosis, which results in lacunar subcortical haemorrage) ; or
3. Rupture of micro aneurysms
   - Haemorrhages can be large such as that associated to amyloid angiopathy (cortical haemorrhage - occurs superficially)
   - Presents as a stroke with similar time course

Question 20

What would the macroscopic appearance be of an old cerebral contusion?

Answer 20

The cerebrum appear flattened as gyri collapse due to scar tissue deposition.

The brain is unable to replace contusion-dependent necrotic tissue with neural tissue; it deposits connective tissue in scar formation.

Question 21

Discuss the effects of missile injuries to the brain

Answer 21

Most common source of missle injury to the brain is via a bullet.

The kinetic energy imparted by a bullet is determined by its projectile velocity.

The diameter of brain damage is much larger than the projectile body itself - it gives off shock waves in the surrounding soft brain tissue which causes significant damage

Question 22

Characterise diffuse axonal injury

Answer 22

Diffuse axonal injury (DAI) refers to the damage incurred by axons as a result of direct mechanical forces - tends to affect deep white matter tracts regions of the brain.

The corpus callosum is particularly vulnerable to DAI.

At the microscopic level, silver stains demonstrate evidence of axonal injury. Axonal swellings are observed due to the build up of proteins, neuroflaments etc that can’t be delivered to axonal terminals due to damage of the axon itself. Focal haemorrhagic lesion tend to also be present.

Question 23

Characterise diffuse vascular injury

Answer 23

Diffuse vascular injury is the rupturing of tiny vasculature throughout the cerebrum as result of mechanical force

Question 24

What are the long term, macroscopic changes in pathology to the brain as a result of diffuse axonal injury?

Answer 24

Thinner white matter regions/tracts

and

Dilated ventricles

Question 25

How do vetebral fractures/dislocations cause spinal cord pathology?

Answer 25

Vertebral fractures/dislocations can cause severe acute spinal cord compression when hard bone imparts pressure upon the delicate spinal cord. Results in a thinned spinal cord and haemorrhaging at the site.

Complications of acute spinal cord compression:

• Get further injury along the spinal cord away from compression site of injury due to hamorrhaging blood compressing nerves within the confines of the spinal cord.

Question 26

What are common long-term sequelae of brain trauma?

Answer 26

Infections

• When barriers to the brain are disrupted/opened during trauma

**Hydrocephalus **

• Neurologic disorder that is caused by a disruption in the balance between the formation, flow, or absorption of CSF in the brain, resulting in an increase in the volume that the CSF occupies in the CNS
• Results most commonly following TBI’s due to scar tissue blocking reabsorption of CSF into subarachnoid spaces.
• Dilated ventricles observed.

Epilepsy

Chronic Traumatic Encephalopathy

• Is a dementing illness that develops after TBI due to neuronal loss and brain atrohpy.
• Is associated to the abnormal deposition of Tau protein + A-beta plaques in brain cortex.

Question 27

What is a normal intracranial pressure?

Answer 27

Normal ICP = 1-15 mmHg

Emergency mmHg = >25 mmHg

Question 28

List possible causes of raised ICP

Answer 28

1. Trauma/Contusions
2. Tumour
3. Infarction
4. Haemorrhage
5. Infection
6. Cerebral oedema
7. Overproduction, obstruction to flow or absorption of CSF (e.g contusion scarring of CSF pathways or CSF producing tumours)

Question 29

Discuss the principles, course and consequences of raised ICP

Answer 29

Cranial contents consist of brain, CSF and blood

• These contents are contained within a fixed container - expansion of any of them, or introduction new contents, elevates the pressure within the cranium.
• ~ 150mL each of blood and CSF - rest brain.

The initial response to an expanding brain lesion is the expulsion of as much CSF and venous blood as possible to compensate for the lesion. The ICP rises when this can’t be done any further.

As a result of raised ICP, herniation of brain tissue can occur through dural openings.

Danger: as ICP approaches cerebral arterial pressure, brain perfusion ceases.

• CPP = MAP - ICP

Question 30

What are the two main types of cerebral oedema?

Answer 30

1. Vasogenic Cerebral Oedema

• Increased extracellular fluid due to blood brain barrier disruption with increased vascular permeability (following inflammation, necrosis or neoplasms)
• Predominantly involves white matter
• Is steroid susceptible - can be treated with steroids

2. Cytotoxic Cerebral Oedema

• Increased intracellular fluid secondary to neuronal, glial of endothelial cell membrane injury.
• Generally a result of hypoxic/ischemic insults like stroke
• Involved white and grey matter
• Not responsive to steroid treatment

Question 31

What are the signs and symptoms of raised ICP?

Answer 31

_Symptoms: _

• Headache
• Vomiting
• Blurred vision

Signs:

• Depressed conscious state
• Cushings triad (hypertension, bradycardia and irregular respiration):
• (Decreased cerebral perfusion triggers a reflex increase in BP; Baroreceptors respond to this increase in BP causing a reflex bradycardia; Compression of respiratory centers in the medula causes irregular respiration)
• Papilloedema (if ICP recent onset)
• Pupil changes – dilation unilaterally or bilaterally (features of herniation)

Late signs:

• Abnormal posturing (decerebrate and decorticate) – late sign
• Brain ischaemia symptoms such as dellirium and LOC

Question 32

Describe the three main types of herniation in the brain.

What structures are endangered by each of the herniations?

Answer 32

_*Subfalcine (cingulate) herniation *_occurs when unilateral or asymmetric expansion of a cerebral hemisphere displaces the cingulate gyrus under the falx cerebrei. This may lead to compression of the anterior cerebral artery and its branches or the corpus callosum (risk of infarct to corpus callosum)

Transtentorial (uncal) herniation occurs when the uncus (parahypocampal gyrus) herniates under tentorium cerebelli, which compresses the contralateral cerebral peduncle (ipsi hemiparesis), stretches the ipsilateral III CN (ipsi, mydriasis) and compresses the PCA resulting in occipital lobe infarct. The midbrain is compressed therefore affecting the ascending reticular activating system resulting in LOC.

Tonsilar herniation occurs when tonsils of the cerebellum are displaced into the foramen magnum. This compresses the medulla and compromises life threatening cardiovascular and respiratory centres.

Question 33

Discuss the timeline of events which occur in the response to PNS axon injury

Answer 33

Normal neuron

• Central nucleus and dense Nissl substance (granules of rER with rosettes of free ribosomes for protein production)

Up to 2 week post injury

• Peripheral nucleus and loss of Nissl substance
• Wallerian Degeneration
  
  • Degeneration of axon and myelin sheath distal to the site of injury
  • Debris is phagocytosed by macrophages
  • Muscle fibre atrophy of this neuron -> use it or lose it principle​

​Up to 3 weeks post-injury

• Scwann cells proliferate to form a compact cord
• Growing axons penetrate the Schwann cell cord
  
  • Some sprouting may occur which will largely be unuseful - only need one branch to reinnervate the target lost by injury
• Muscle fibre atrophy

3 months post-injury

• Successful regeneration
• Electrical activity restored
• Muscle fibre regeneration

Question 34

What occurs in unsuccessful regeneration of the PNS nervous injury?

Answer 34

If the PNS unsuccessfully regenerates, neuroma formation may occur.

Neuroma formation refers to aberant axon growth that can’t find the right target of re-innervation. It results in a bundle of nerve fibres with no innervation which can cause severe pain when spontaneously stimulated.

Question 35

Why is PNS repair faster if an axon is crushed rather than cut?

Answer 35

Schwann cells and extracellular matrix in distal axon segments provide a guide in both iinstances but is more continuous in a crush injury.

The more precise the allignement; the better the regeneration and recovery of function is. Cutting an axon misaligns the proximal and distal axons more than simply crushing them.

Microsurgery is the main therapeutic approach to PNS injury.

Question 36

Discuss the biological timeline of events involved in CNS neural injury

Answer 36

Primary Injury

Immediate physical damage and cell loss. Remove the primary cause of the damage and prevent further damage

Secondary Injury

Minutes to Hours: Degenerative insults:

• Ischemia
• Ca²⁺influx
• Lipid peroxidation and free radical production
• Glutamate excitotoxicity
• BBB breakdown

Hours to days/weeks: Immune response:

• Immune cell infiltration
• Microglial activation
• Cytokines, chemokines and metalloproteases

Days to weeks: Degeneration:

• Axonal degeneration
• Demyelination
• Apoptosis - neuronal and oligodendrical
• Phagocytosis of debris
• Astrocytic gliosis and glial scarring
• Cavity formation and meningeal fibroblast migration

Question 37

What changes to astrocytic function result in the formation of the glial scar?

Answer 37

In response to CNS injury, there is an upregulation of astrocyte cytoskeletal protein GFAP (glial fibrillary acidic protein); which is induces astrocytic gliosis

As a result of this, astrocytes:

• Hypertrophy
• Proliferate
• Interdigitate their processes to form more of a barrier
• Secrete cytokine and growth factors
• Secrete ECM that is highly inhibitive of axonal regrowth
• Upregulate expression of developmental guidance molecules.

All of these factors contribute to the formation of the glial scar. The glial scar forms a barrier betwwen the injury site and undamaged tissue (protective) but also prevents the regeneration of axons through this area of injury.

Need to manipulate a balance between protection and regeneration of injured CNS tissue

Question 38

What prevents axonal regeneration in the CNS?

What can be done to resolve this?

Answer 38

1. Lack of Trophic Support

• Encourage axons to grow by providing growth promoting factors
  
  • Neurotrophins

​2. _Axon regrowth inhibited by the injury environment _

• Inhibit growth blocking factors
  
  • Astrocytic gliosis & glial scar
  • Myelin inhibitors
  • Developmental guidance molecules
    *

Question 39

Discuss the impact of myelin inhibitors in preventing axonal regrowth

Answer 39

Myelin inhibitors located on the myelin debris of oligodendricytes are inhibitory molecules in the injury environment that bind to regrowing axons/dendrites and repress their growth cones.

Myelin proteins are inhibitive of regrowth under normal physiology in order to prevent abberant sprouting of neurons.

Myelin proteins include: Nogo, MAG (myelin associated glycoprotein) and OMgp (oligodendrocyte/myelin glycoprotein).

These proteins all bind to Nogo receptors and activate the Rho signalling pathway which neuronal growth cone formation. Thus stunts regrowth

Question 40

Discuss the impact of axon guidance molecules in the inhibition of axonal regrowth of CNS injury

Answer 40

Axon guidance molecules promote, repel or guide axon growth - typically during developmental stages of human life.

Many of these axon guidance molecules are upregulated or re-expressed following CNS injury (particularly via astrocyte production); the majority of which are repellant and inhibitive of axonal regrowth.

Ephrins/Eph are a particular type of axon guidance molecule that is up-regulated by reactive astrocytes in the injury environment. EphA4 and ephrinA5 are significant axonal repellants.

These axon guidance molecules converge on the Rho kinase pathway to affect growth cone regulation

Question 41

What is the importance of the Rho Kinase pathway in axonal regrowth in CNS injury?

Answer 41

Rho kinase pathway is an important mechanism of neuronal growth cone regulation.

It lies downstream to a number of growth inhibitor receptors (NOGO, Ephrin, Semaphorin etc.). It is for this reason that it is a promising target of CNS injury therapeutics.

Activation of the Rho pathway by these receptors results in stunted activity of the neuronal growth cone and suppression of regeneration.

Rho inhibitors are under clinical trial currently

Question 42

Discuss the possibility of using stem cells to repair an injured CNS

Answer 42

There are two plausible ways of utilising stem cells to replace neuronal cells lost to CNS injury:

1. Activation of endogenous CNS stem cells

There are two main neurogenic regions of the brain that contain neural stem cells:

• Subventricular zone of the lateral ventricle
• Subgranular zone of the dentate gyrus in hippocampus (involved in memory/learning)

These areas don’t normally repair CNS because they have difficulty in proliferating, migrating, differentiating and surviving to be effective. Therapies are in development to try to facilitate the use of these cells in repairing the CNS.

2. Transplantation of stem/progenitor cells

Culturing embryonic stem cells, induced pluripotent stem cells and endogenous adult stem cells for transplantation into affect sites to replace lost neuronal cells.

Question 43

What complications are likely to be encountered even if an effective therapy to regenerate neurons is available?

Answer 43

It is likely that a combination of therapies will be required.

Unsure whether axons that regenerate and make connections will be a) topographically accurate (correct target) or b) functionally acurate.

Physical therapy and muscle/neuronal activity be important to functional improvement.

Question 44

What differences between the CNS and PNS account for their different responses to nervous injury?

Answer 44

Question 45

What is the definition of a stroke?

Answer 45

Stroke is a clinical term refering to the development of a focal or global neurological deficit relating to a vascular event.

The vascular event can be variable in type, position and severity.

Note: transient clinical events may occur as a result of vascular events or “silent” vascular events may occur where there are no observable/noticable impacts of the event of function.

Question 46

What pathological processes are involved in stroke?

Answer 46

Infarction (75%)

• Death of tissue due to inadequate blood flow

Intra Haemorrhage (20%)

• Tissue injury due to the rupture of blood vessels and subsequent loss of blood

Non-traumatic Subarachnoid Haemorrhage (5%)

• Escape of blood primarily into the subarachnoid space

Question 47

Discuss the epidemiology and risk factors for cerebral infarction/stroke

Answer 47

Stroke is the third leading cause of death (10% of all deaths)

Significant incidence of morbidity in survivours -> lead disabled lives of varying severity.

Risk factors include:

• Aging
• Hypertension
• Cardiac Disease (e.g. Atrial Fibrillation)
• Hyperlipidaemia
• Diabetes Mellitus
• Hypercoagulable States
• Smoking
• Obesity

Question 48

Examine the mechanisms of cerebral infarction

Answer 48

Cerebral infarction is the necrosis of cerebral tissue in a particular vascular distribution due to:

1. Vessel occlusion by embolus (most common)
2. Inadequate blood supply due to narrowed vessel lumen

• Atherosclerosis
• Thrombosis
• Hypertensive vessel thickening
• Amyloid angiopathy

3. Severe hypoperfusion due to cardiac failure

Question 49

What types of vascular events affect the different kinds of vessels in cerebral tissue?

Answer 49

All vessels = cardiac failure

Large artery occlusion = Thrombotic < Embolic

Small vessel occlusion = Thrombotic and embolic

Venous occlusion = Thrombotic

Question 50

Describe thrombotic endocarditis and it’s potential to result in stroke pathology

Answer 50

**Thrombotic endocraditis **is the deposition of a coagulative mass of thrombotic material onto the valves of the heart.

It occurs as a result of hypercoagulative states, deformed valves or certain types of infection.

The mass can culture microbes (infective endocarditis) which can cause underlying damage to of the valve.

There is significant potential for parts of these masses to embolise and occlude vessels downstream; including that of the cerebrum.

Question 51

What is the significance of probe-patent interatrial septum to cerebral infarctions?

Answer 51

P**robe-patent interatrial septum **is congenital deficiency in the inter-atrial septa septa of the heart that occurs in 1/3 of all people.

This communication allows for a potential thrombus to pass from the right atrium to the left atrium. The **venous system is the most common site of emboli formation **and this deficiency provides a route to arterial system rather than the pulmonary system where a pulmonary embolus was more likely to form.

In these cases, the propensity to have cerebral emboli is elevated.

Question 52

What are the common sites of atherosclerosis in the circle of Willis?

What features of the circus of Willis minimises the impact of occlusions in its distribution?

Answer 52

The three most common sites of athersclerosis include:

1. Basillar Artery
2. Proximal Middle Cerebral Artery
3. Terminating ends of Internal Carotid Artery

The Circle of Willis have reasonably sized vessels communicating between the basillar/vertebral and internal carotid arterial systems which allows for the compensation of blockages of the main branches.

Question 53

What are the two ways atherosclerosis can cause thrombosis?

Answer 53

1. Luminal narrowing
2. Ulceration of plaques

Question 54

What is a carotid endarterectomy?

Answer 54

Carotid endarterectomy is an operation conducted to prevent ulcerated or stenotic atherosclerosis of the common/internal carotid artery from causing a cerebral infarction -> prophylactic

Athersclerosis at the biforcation of the common carotid is a common pathology. It causes narrowing, restricting flow or give rise to emboli that result in strokes.

Question 55

Describe the pathological processes that occur over time following a cerebral infarction

Answer 55

First 6 Hours

There is little change in appearance during the first 6 hours of irreversible injury.

6-48 hours

• Ischemic neuronal change with both cytotoxic and vasogenic oedema predominating = Swelling
• Loss of the demarcation between white- and gray matter structures.
• Endothelial and glial cells, mainly astrocytes, swell, and myelinated fibers begin to disintegrate - cell membrane breakdown
• Evidence of herniation if severe enough
• Neuronal changes
  
  • initially swell but ultimately shrink
  • become highly eosinophilic
  • nucleus condenses/pyknosis
  • nucleus eventually lost.

Days to Weeks

• Swelling resides
• Tissue undergoes liquefactive necrosis
  
  • high volume of necrotic material and macrophages removing debris histologically
  • porrige like consistancy macroscopically

Months to a year

• Scarring
• Formation of cystic spaces filled with CSF

Question 56

What typically causes the death of patients who have suffered a cerebral infarction?

Answer 56

Cerebral infarctions can directly cause death by:

1. Damaging vital centres of the brainstem
2. Cerebral swelling / raised intracranial pressure (herniation risk)

But most commonly, patients tend to die from causes secondary to the stroke event - these patients tend to have co-morbidities with similar risk factors to stroke. This includes:

1. Pneumonia
2. Cardivascular Disease
3. Pulmonary thromboembolism

Question 57

What are the common causes of intracerebral haemorrhage?

Answer 57

Common pathologies include:

1. Hypertensive small vessel disease
2. Amyloid Angiopathy (congophilic angiopathy)
3. Blood disorders
4. Tumour
5. Vasculitis
6. Vascular malformation
7. Drugs (by causing hypertension or causing vasculitis)

Question 58

What is a hypertensive haemorrhage?

Answer 58

Hypertensive haemorrhages are characterised by the presence of **small vessel disease = hyaline artiolosclerosis. **

It tends to occur in deep grey matter (and some deep white matter) but no cortex areas:

• Basal ganglia/thalamus
• Lobar white matter
• Cerebellum
• Pons

Hyaline arteriolosclerosis results from chronic hypertension. It leads to the deposition of hyaline-like plaques in the walls of small arteries. This causes wall thinckening and narrowing of the lumen.

Depositions within the wall makes it weaker and it dilates or “balloons”. This predisposes the vessel to rupturing -> resulting in a cerebral haemorrhage.

Note: hyaline arteriolosclerosis can also lead to thrombosis at the earlier stages where the lumen narrows.

Question 59

Discuss cerebral amyloid angiopathy (CAA)

Answer 59

**Cerebral amyloid angiopathy (CAA) **involves the deposition of amyloidogenic peptides, particularly A-beta Amyloid (same as Alzheimer’s disease), in the walls of small and medium meningeal and cortical blood vessels = superficial blood vessels of the cortex

Deposition of A-beta plaques in the walls of these vessels can weaken them and cause haemorrhage.

This condition is associated to superficial cerbral haemorrhages - tend to keep reoccuring over time and are affect people of varying ages.

These CAA cerebral haemorrhages are highly associated to **Alzheimer’s Disease **(same plaques)

Question 60

What would you expect to see in a patient with multifocal synchronus haemorrhages?

Answer 60

It is highly unlikely that multiple haemorrhages would develop concurrently as a result of hypertensive or CAA haemorrhages.

It is more likely to be a systemic problem.

Presentations like this are typical of coagulopathies of the blood leading to the thrombosis of small vessels in any region of the brain.

Question 61

Discuss the pathogenesis of cerebral haemorrhage resulting from congenital arteriovenous malformation

Answer 61

Congenital arteriovenous malformation involves the improper positioning of blood vessels within a blood supply circuit.

In cerebral haemorrhages, arterioles with high pressure blood directly pass this blood to venous vessels without a any capillary formations. The venules are unable to handle this pressure and rupture to cause haemorrhage.

Question 62

Discuss the causes of subarachnoid haemorrhages (non-traumatic)

Answer 62

Subarachnoid haemorrhages (non-traumatic) tend to result from vessels before they have penetrated the cerebral tissue. They tend to be larger vessels - such as branches of the Circle of Willis.

Common causes include:

1. _Rupture of Saccular/Berry aneurysm _
2. Rupture of other types of aneurysm

• mycotic (infective)
• atherosclerotic

3. Extension of intracerebral haemorrhage that leaks into the subarachnoid space.

Question 63

What are the risk factors for developing a saccular aneurysm?

Answer 63

• Sex and Age (Male and Elderly)
• Polycystic kidney disease
• Coarction of Aorta
• Type III collagen deficiency (and similarly)
• Hypertension
• Smoking/alcohol

Question 64

What are saccular aneurysms?

Answer 64

**Saccular aneurysms **are large “berry-like” aneurysm at sites of congenital weakness in involved vessels -> absence of smooth muscle and internal elastic lamina.

They tend to occur at **sites of arterial bifurcation **and in the anterior cerebral circulation more commonly than the posterior cerebral circulation.

The most common sites include:

1. Middle Cerebral Artery (MCA) bi/trifurcation
2. Junction of ICA and Posterior Communicating Artery
3. Anterior Communicating Artery (ACA)

Question 65

What are the complications arising from a ruptured saccular aneurysm?

Answer 65

1. Subarachnoid Haemorrhage
2. Cerebral oedema and raised ICP
3. Vasospasm and Infarction

• blood products in the subarachnoid space are spasmogenic
• cause vasoconstriction of cerebral vessels -> ischemia and infarction to distal supply.
• need to clip aneurysm ASAP to prevent blood loss

4. Ventricular obstruction / hydrocephalus
   * Healing fibrosis that occludes the openings of the ventricular system into the subarachnoid space -> back up of CSF to expand ventricles -> raised ICP

Question 66

What neurobiological and cellular mechanisms lead to the formation of epileptic neuronal networks?

Answer 66

1. Loss of inhibitory neurons & gain of excitatory neurons (aberrant sprouting connections
2. Alterations in intrinsic cellular excitability
3. Alteration in synaptic transmission
4. Alterations in the neuronal environment (glial cells)

Question 67

Why is the hippocampus an important talking point in the study of epilepsy?

Answer 67

The hippocampus - part of the medial temporal lobe - is a particularly sensitive structure to induce epileptic activity in humans and animal models.

It has four subregions: dentate gyrus, CA1, CA2 and CA3 that all show unidirectional circuitry

In humans and animal models of mesial temporal lobe epilepsy (a common form of epilepsy) epileptogenic remodelling demonstrates a consistent pattern known as mesial temporal sclerosis:

• Cell loss in CA1, CA3 and dentate gyrus region
• Mossy fibre sprouting
• Gliosis

Question 68

Does epileptogenic remodelling cause epilepsy; or is it a result of epilepsy?

Answer 68

Seizure themselves are thought to accelerate the pathology of aberrant epileptic networks - making further seizures common.

It is uncertain whether the neurobiological changes seen in epileptic circuits cause epilepsy or the result of epilepsy itself.

Question 69

Discuss the relationship between the incidence of epilepsy and age

Answer 69

The distribution of epilepsy incidence is bimodal

It is more common in the young (children and adolescents) and the elderly

The aetiology of epilepsy differs between the age groups:

Infancy/early childhood: due to congenital/perinatal CNS insults

Late childhood/early adulthood: idiopathic/genetic causes

Adult/elderly: most symptomatic epilepsy; caused by a variety of insults including degenerative disease, tumours, trauma and vascular events.

Question 70

List the most common lesions associated with partial epilepsy on MRI’s

Answer 70

Most common to least common:

1. Mesial temporal sclerosis
2. Malformations of cortical development
3. Low grade tumours
4. Vascular malformations
5. Encephalomalacia

Question 71

What is the most common pathology seen in an MRI of an adult patient with partial epilepsy?

Answer 71

Mesial temporal sclerosis is the most common pathology found in MRI’s of adult patients of partial epilepsy.

It is refractory (unaffected) to medical therapy but… good prognosis with _epilepsy surgery _

Question 72

Describe two common forms of cortical malformations that are associated with epilepsy

Answer 72

Focal cortical dysplasia

Focal regions of disturbed cortical development and architecture.

• Aetiology is unknown - not genetic
• MRI shows thickening of cortex, loss of demarcation between white and grey matter, gyrus abnormalities and increased T2 signals

Periventricular Nodular Heterotopia

Generalised malformation due to abnormal neuronal migration

• Nodular masses form of grey matter lining the ventricles (bilateral or unilateral)
• Cortex and neurological functional normal
• Inherited (X-linked or autosomal recessive)

Question 73

Describe the role of low grade tumours in partial epilepsy

Answer 73

Low grade tumors are implicated in 15% of patients with partial epilepsy.

Most common cause of new onset partial seizures in adults 35-55 y.o

Gliomas (most common 88%), meningiomas and neuroepithelial tumors are the main types

Tend to occur in cortex > subcortex

Question 74

Describe the incidence of vascular lesions causing partial seizures

Answer 74

Vascular lesions are responsible for 10% of medical resistant partial epilepsy - is difficult to control

Two types of vascular lesions are particularly linked:

Arteriovenous malformations

Congenital vascular abnormalities consisting of communicating arteries and veins without intervening capillary beds.

Cavernomas

Tangled mass of tightly arranged abnormal vessels made of common hypocellular walls

• seizures common (40-70%) but haemorrhage rare

Question 75

Discuss focal encephalomalacia and its association to partial seizures

Answer 75

Focal encephalomalacia are focal lesions (soft or loss of tissue) that result from previous destructive insults such as trauma, stroke, infection etc.

Question 76

What treatment options are available to treat epilepsy?

Answer 76

Anti-epileptic drugs

• Treat the symptoms; not the underlying epileptic condition
• Decreases the frequency and severity of seizures
• Treatments required for years - often a lifetime

Surgery

• Can only be attempted in patients with focal epilepsy where the origin of seizures can be localised to a brain section. This section can then be resected if safe to do so.
• 80% success in appropriate cases

_Neurostimulators _

Dietary

Question 77

What deficiencies in current epilepsy treatment need to addressed in the future?

Answer 77

Any future advances in anti-epileptic treatment will be a multi-faceted approach that addresses:

1. Medically refractory seizures are the most common types of seizures - need to treat them
2. Currently medication have poor tolerability - cognitive slowing etc.
3. No anti-epileptogenic or disease modifying treatments - all drug therapies treat the symptoms
4. Better treatment of co-morbidities (psychiatric and cognitive deficits)

Question 78

What are unstable repeat expansions?

Answer 78

**Unstable repeat expansions **are a class of genetic conditions characterised by an expansion of a segment of DNA within a specific gene.

The expansion consists of repeating units of three or more nucleotides in series.

They are a form of **dynamic mutation **as the size of expansion varies person to person; genertation to generation.

• Expansion size increases in subsequent generations of progeny -> this is known as anticipation.
• Anticipation is associated with earlier disease onset and/or greater disease severity

Question 79

What is the mechanism by which unstable repeat expansions are accumulated?

Answer 79

Although not certain, it is though that slipped mispairing during DNA replication contributes to expanded repeat regions.

1. Replicating strand detaches inappropriately from the template strand during DNA replication
2. This leads to the replicating strand slipping from its proper allignment to the template strand by a single repeat length - it loops out.
3. An additional replicating repeat is sysnthesised to replace it.
4. The newly synthesised strand contains an extra repeat.

Question 80

What effect does the site of an unstable expanded repeat have on gene expression?

Answer 80

There are generally three outcomes of unstable expanded repeats:

1. Non-coding repeats causing a loss of protein function

• as a result of impaired transcription of the affected gene protein
• example: Fragile X and Friedreich ataxia

2. Non-coding repeats that confer novel properties to the RNA

• leads to RNA with toxic gain of function
• example: Myotonic dystropy (1 and 2)

3. Repeats in a codon that confer novel properties in the affected protein

• Novel gain of function due to the production of a modified protein which overrides the normal protein function
• example: Huntington’s disease, spinocerebellar ataxia

Question 81

Provide a basic epidemiological overview of Huntington’s disease

Answer 81

Huntington’s disease is an autosomal dominant neurodegenerative disease

It affects 1/10,000-20-000 people

It is late onset generally; small proportion of early onset in severe cases.

Main features include:

• Movement/motor disorders
• Cognitive disorder
• Psychiatric disorder

Question 82

What are the clinical signs of Huntington’s Disease?

Answer 82

_Early features/prodrome _

Clumsiness, agitation, irritability, apathy, anxiety, disinhibition, delusions/hallucinations, abnormal eye movements and depression

Middle features

Involuntary movements, chorea, trouble with balance and walking, trouble with activities that require manual dexterity, slow voluntary movements, general weakness, weight loss, speech difficulties (dysarthria) and stubbornness

Late features

Rigidity, bradykinesia (difficulty initiating and continuing movements), serious weight loss, inability to walk, inability to speak, danger of
choking on food, inability to care for oneself

Question 83

Discuss the genetic basis of Huntington’s Disease

Answer 83

Huntington’s disease results from expansion in the HTT (HD) gene found in chromosome 4.

• Repeat region located within exon 1 (of 6)
• Involves repeat of CAG -> coding polyglutamine

The normal protein product is Huntingtin (HTT)

• has a role in transcription, intracellular transport, intracellular signalling and reducing apoptosis

Expanded CAG HTT product (polyQ-huntingtin) has a toxic effect in basal ganglia

• particularly spiny neurons

Early affects appear only in the brain despite the gene being expressed throughout the body

• there is sometyhing specific to the brain environment that exaggerates onset and severity in the brain

Question 84

Discuss the pathology of Huntington’s Disease

Answer 84

Huntingtons Disease results in the progressive degeneration and loss of medium spiny neurons in the striatum of the basal ganglia

PolyQ-Huntingtin is cleaved by caspases and other enzymes to generate toxic N-terminal fragments with altered conformations.

These fragments form aggregates and nuclear inclusions. Note that the nuclear inclusions may actually be a protective cellular response to the disease.

Loss of function of normal HTT and possible RNA toxicity might also contribute to pathogenicity,

Question 85

Discuss the relationship between Huntington’s Disease genotype and phenotype

How is HD tested?

Answer 85

Normal = <26 repeats

‘Normal’ but increased risk of offspring HD anticipation = 27-35

Zone of reduced penetrance = 36-39

Affected = >40

Classically, HD was tested using PCR-electrophoresis-autoradiography in order to determine repeat numbers.

Modernly, PCR–fragment analysis-electrophoresis-fluorescence detection used.

Question 86

Provide a basic epidemiological overview of Freidreich Ataxia

Answer 86

**Freidreich Ataxia **is an autosomal recessive dynamic mutation to intron non-coding regions.

It affects 2-4/100,000

Carrier frequency of 1/60 (1/100 in Indo-Europeans)

Age of onset is around puberty (mean age 10) ; usually less than 25 years old.

Main features include:

1. Progressive limb and gait ataxia
2. Cardiomyopathy
3. Diabetes mellitus

Question 87

Discuss the genetic basis of Freidreich Ataxia

Answer 87

**Freidreich Ataxia **involves the GAA repeat expansion of the FXN gene found on Chr 9

Unstable repeat expansion occurs within **intron 1 **

• causes abnormal DNA structure and/or induces reduced protein production

Expansion accounts for 94-98% of cases

• Compouns heterozygotes with GAA repeats and other single point mutations comprise remaining 2-6%

Normal protein is produced; but there is insufficient amounts of it due to altered gene expression of the intronic DNA.

Leads to mitochondrial mediated oxidative damage (via Iron)

Question 88

Discuss the relationship between genotype and phenotype in FA

Answer 88

Normal = 5-33 repeats

Pre-mutation range = 34-65 reppeats

Affected = 66-1700 repeats

Note: alleles longer than 27 GAA triplet repeats are often interupted by a (GAGGAA)n sequence that is protective -> stabilises the allele

Question 89

Provide a basic epidemiological overview of Spinocerebellar Ataxia

Answer 89

**Spinocerebellar Ataxia (SA) **is an autosomal dominant unstable expanding repeat.

There are various types of SA (~35 described; 10 due to unstable repeat expansions) and their frequency varies across populations

Generally a late onset neurodegenerative disease

Main features:

• Progressive degeneration of the cerebellum, brainstem and spinocerebellar tracts
  
  • leading to gait, hand, coordination, speech and eye movement deficits
• Phenotypic variation

Question 90

How is Spinocerebellar ataxia tested?

Answer 90

Classical PCR-Gel electophoresis or Modern PCR- fragment analysis

Question 91

What ethical issues should be considered in predictive (pre-symptomatic) genetic testing

Answer 91

• Different implications in laboratory diagnosis of genetic disease
• Implications for not only patient, but also other family members
• Formal consent, genetic counselling and confidentiality issues, especially with predictive testing (restricted access to results)
• Insurance (life, disability) implications (NB family history)
• Predictive testing in children not usually encouraged (NB ‘mature minors’)
• Prenatal testing, including pre-implantation genetic diagnosis (PGD) possible – need to know mutation/haplotype in parent

Question 92

What are the risk factors that predispose to Alzheimers disease?

Answer 92

Age

• exponential doubling of incidence with each decade after age 50

Familial/Genetic

• Trisomy 21
• Apolipoprotein E
• APP mutations
• Gene dosage of A-beta/APP gene

Education

Head Trauma

Smoking

Vascular Disease

Diabetes

Question 93

Describe the Amyloid Cascade Hypothesis

Answer 93

Amyloid Cascade Hypothesis describes protein aggregation in Alzheimer disease.

Amyloid precursor protein (APP) cleavage by α-secretase and γ-secretase produces a harmless soluble peptide, whereas amyloid precursor protein cleavage by β-secretase and γ-secretase releases Aβ peptides, which form pathogenic aggregates and contribute to the characteristic plaques and tangles of Alzheimer disease

Question 94

What is thought to cause toxicity in Alzheimers disease?

Answer 94

Synaptic toxicity is thought to be mediated by A-beta synaptic toxicity.

This arises from A-beta monomer dispersing in the brain onto the membrane surfaces of the neuron at intra- and extra-synaptic sites.

Question 95

What is the relevance metal -protein attenuating compound

Answer 95

Metal -protein attenuating compound (MPAC) has been shown effective in sequestering and reducing the A-beta load in mouse models of Alzheimers Disease

Question 96

Discuss the relevance of ¹¹C-PIB for A-beta imaging of AD patients

Answer 96

¹¹C-PIB is a radioactive ligand that binds to A-beta amyloid in the brain allowing the viewing and quantification of A-beta.

Neocortical imaging intensity of¹¹C-PIB greater than 1.5 is indicative of Alzheimers Disease

Studies investigating this imaging method as a diagnostic tool for AD concluded that there is approximately 30 years between complete normality and clinical AD

Alternatively, measurements of A-beta in the CSF can be reflective of cerebrum levels.

Question 97

What is Kuru?

Answer 97

Kuru is an aggressive cerebellar degenerative condition as a result of a prion disease transmitted by canabolism in Kuru region of Papua New Guinea.

Was characterised by trembling and shaking (the definition of Kuru)

It mainly affected females and children

Implementation of public health and awareness surrounding food processes has all but eradicated the disease over the last 50 years.

Question 98

What is variant Creutzfeldt-Jakob Disease?

Answer 98

Starting in 1995, a series of cases of a CJD-like illness came to medical attention in the United Kingdom.

This illness was different from typical CJD in several important respects: the disease affected young adults, behavioral disorders figured prominently in the early stages of the disease, and the neurologic syndrome progressed more slowly than in individuals with other forms of CJD.

The neuropathologic findings and molecular features of these new cases were similar to those of CJD, suggesting a close relationship between the two illnesses, with multiple lines of evidence indicating that the new variant form of CJD was linked to exposure to bovine spongiform encephalopathy

Question 99

What molecular pathology is observed in vCJD/BSE?

Answer 99

Pathogenesis of prion disease vCJD/BSE involves the conversion of PrP^cto PrP^res.

α-helical PrP ^c may shift to the β-sheet PrP ^sc conformation - either spontaneously as a result of genetic mutations to PRNP gene that encodes PrP^c or transmissible prion diseases.

PrP^res may also be acquired from exogenous sources, such as contaminated food, medical instrumentation, or medicines. Once present, PrP^sc converts additional molecules of PrP^c into PrP^sc through physical interaction, eventually leading to the formation of pathogenic PrP^scaggregates

Question 100

What is of concern in regards to transmissible spongiform encephalopathy / vCJD?

Answer 100

It is now reasonable to assume that vCJD patients blood is infectious; and that sCJD (secondary) blood may be infectious.

Estimated incubation period is 6-15 years; initial outbreak of BSE was ~1988-1993 in UK. This suggest a peak blood infectivity at the current time.

Have had the primary bovine to human phase; entering a secondary human to human transmission period now that will peak in 2020

Question 101

**What role does a-synuclein have in Parkinson’s Disease? **

Answer 101

The first gene to be identified as a cause of autosomal dominant PD encodes α -synuclein, an abundant lipid-binding protein normally associated with synapses.

• normally a soluble protein that sits in the vesicular membrane
• mutated a-synuclein interactions with metal dopamine cause it to abnormal fold into non-soluble aggregates

This protein is a major component of the Lewy body, which is the diagnostic hallmark of PD.

• Lewy bodies are large inclusions of a-synuclein in the cytoplasm of cells of the Substantia Nigra

The occurrence of disease caused by changes in gene copy number implies a gene dosage effect, and suggests that polymorphisms in the α-synuclein promoter that alter its expression may influence the risk of PD.

Like Aβ in Alzheimer disease, α-synuclein has been demonstrated to form aggregates; of these, small oligomers appear to be the most toxic to neurons.

Question 102

How can you monitor/measure the progression of Parkinson’s Disease?

Answer 102

You can monitor the progression of AD by measuring the levels of VMAT 2

**VMAT 2 **is a protein that normal a-synuclein contributes to the formation of.

Abnormal a-synuclein doesn’t form the VMAT 2 protein and levels of it drop.

Question 103

What is catatonia?

Answer 103

Catatonia is motor immobility as evidenced by cataplexy or stupor

Patients are incapable of initiating movements -> maintain postures and positions.

Still don’t understand how this occurs