Neuropathology

Question 1

What is the central nervous system?

Answer 1

The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord.
Where does the CNS stop and the PNS start?
The dorsal root ganglion

Question 2

Where does the CNS stop and the PNS start?

Answer 2

The dorsal root ganglion

Question 3

What is the peripheral nervous system?

Answer 3

The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord.

It includes:
the cranial nerves, spinal nerves and their roots and branches, peripheral nerves, and neuromuscular junctions.
The anterior horn cells, although technically part of the central nervous system (CNS), are sometimes discussed with the peripheral nervous system because they are part of the motor unit

Question 4

What are the main cells of pathological significance in the central nervous system?

Answer 4

NEURONS
ASTROCYTES
act as specialized support cells
OLIGODENDROCYTES
which form myelin
MICROGLIA
the resident cells- macrophages of the CNS.

Due to the compact nature of the nervous system, even small lesion may produce severe functional disturbances.

Importantly, any neurons that are lost, cannot be replaced as they lack capacity for cell division.

Question 5

What is raised intracranial pressure?

Answer 5

Occurs when there is swelling in the skull
Severe cerebral swelling is associated with a rise in pressure in the skull > called a RAISED INTRACRANIAL PRESSURE.

Swellings in the brain are particularly dangerous when they lead to local expansion of one part, causing it to shift from one brain compartment to another – a process called cerebral herniation.
There is only a limited amount of space within the skull
Initially, reduction in the size of the ventricles and subarachnoid space occurs, but once this volume is used, further increase in the lesion is associated with a further increase in intracranial pressure.

Question 6

What are the 2 main consequences of intracranial pressure?

Answer 6

Brain structures shift and can become compressed or compromised

The pressure within the skull can be so high that it exceeds the arterial perfusion pressure, leading to brain death.

Question 7

What can cause a Raised Intracranial Pressure?

Answer 7

Bleeding, Neoplasms & swelling (edema) associated with Ischemia.

Question 8

What are the symptoms of intracranial pressure?

Answer 8

Clinically, a patient with raised intracranial pressure may present with:

Vomiting
due to movement of the medulla and stimulation of communication centers
Headache
due to stimulation of pain sensitive nerve endings associated with stretched vessels
Papilledema due to impaired flow of axonal cytoplasm in the optic nerves
due to impaired flow of axonal pressure of the CSF in the optic nerve sheath.

Slow expanding lesions – signs develop slowly; Rapid – within minutes

Following head trauma, it is best practice to observe patients carefully and regularly to detect any early signs of an enlarging brain lesion, termed cerebral herniation.

Pupils are observed for a sluggish pupillary reaction
Due to stretching of the 3rd Cranial Nerve
A fixed dilated pupil is seen in more advanced herniations.
Compression of the 3rd Cranial Nerve
Conscious levels are assessed, as if the brain stem is compressed, there is progressive reduction in conscious level.

Question 9

What are AVM’s: Arteriovenous malformations (AVMs)?

Answer 9

Are developmental abnormalities of blood vessels, which are unusually fragile
They are most common in the cerebral hemispheres, but can be found in the spinal cord.

Clinically, AVM’s are a cause of epilepsy and other focal neurological signs
The major problem with these, if these fragile vessels bleed, it can cause lift threatening intracranial haemorrhage.

Question 10

What are cerebrovascular diseases?

Answer 10

Cerebrovascular Diseases are the third most common cause of death in western countries

It most frequently manifests as a sudden episode of neurological deficit called a stroke.

A stroke is the result of cerebral hemorrhage or cerebral infarction (in the majority of cases)

Question 11

What is the clinical diagnosis of a stroke defined as?

Answer 11

a sudden onset of non- traumatic focal neurological deficit that causes death or lasts for over 24 hours.

Question 12

What is A minor stroke and reversible ischemic neurological deficit (RIND)?

Answer 12

are terms used when recovery of clinical features occurs after a period of time – usually around 24 hours

Question 13

What is a Transient Ischemic Attack (TIA)?

Answer 13

Defined as episodes of non- traumatic focal loss of cerebral or visual function lasting no more than 24 hours.

Question 14

The causes of stroke are divided into 2 main groups - what are they?

Answer 14

Ischaemic (85%)
caused by cerebral infarction
Most common causes originate from outside the cranial cavity: eg. Emboli from the heart, aorta or carotid vessels, and thrombosis in the carotid or vertebral arteries.

Heamorrhagic (15%)
caused by intracerebral & subarachnoid hemorrhage

Routine early imaging plays a key role in distinguishing between hemorrhage & ischemia in patients who present with stroke.

Question 15

True or false? Cerebral Arteries are prone to atheroma, arteriosclerosis and amyloid deposition.

Answer 15

True

Question 16

How does atheroma affect cerebral arteries?

Answer 16

Principally affects the main named cerebral arteries
Generally more severe in the basilar artery (compared to anterior & middle cerebral vessels)
Main complications of of atheroma is thrombosis & aneurysm formation.
A high amount of ischemic events occur in the region of carotid bifurcation

Question 17

How does Arteriosclerosis affect the cerebral arteries?

Answer 17

Affects the small vessels that penetrate the brain
Caused by long standing hypertension or diabetes
which leads to weakening of vessel walls (tunica media), and predisposes to intracerebral hemorrhage.

Question 18

How does Amyloid Deposits affect cerebral arteries?

Answer 18

Especially derived from AB peptide (as seen in Alzheimer’s) is frequently deposited in the cerebral vessels of the elderly- causing amyloid angiopathy.
The cause of 10% of cerebral hemorrhage in patients over the age of 70.

Question 19

What is berry aneurysms?

Answer 19

Berry Aneurysm’s are the most common type of aneurysm in the cerebral arteries.

Berry Aneurysms are small saccular aneurysms that occur in approx. 2% of the population.
Macroscopically they appear as rounded swellings arising from cerebral arteries.
They occur particularly at the branch points of vessels around the circle of Willis
45% occurring in the anterior communicating cerebral artery (more on this in Neuro)

Question 20

How do berry aneurysms arise?

Answer 20

Berry Aneurysms arise because of developmental defects in the internal elastic lamina of vessels.

The stress of the systolic waves cause herniation of the intima, with formation of saccular aneurysms.

This is accentuated by hypertension, and aneurysms are commonly seen in associated with coarctation of the aorta and adult polycystic renal disease.

Question 21

What are the 4 types of ischaemic brain damage?

Answer 21

1. Large Vessel Disease
   Causes regional infarction
   Main mechanism is embolism & thrombosis in large cerebral arteries
2. Small Vessel Disease
   Microinfarcts known as lacunar infarcts
   Caused by arteriosclerosis predisposed by hypertension & diabetes
3. Venous Infarction
   Causes hemorrhagic necrosis in affected area.
   Caused by thrombosis in main cerebral arteries, & are usually associated with abnormal predisposition to thrombosis e.g. thrombophilia syndromes.
4. Global Ischemia
   Widespread neuronal necrosis
   Caused by sustained cardiorespiratory arrest

Question 22

What are the Mechanisms of Hypoxic & Ischemic Damage?

Answer 22

Hypoxic & Ischemic damage to the brain results in failure to supply energy sources.
Neurons have small metabolic reserves and are extremely sensitive to energy deprivation.

Examples: Failure of blood oxygenation
Due to: Severe Respiratory Disease, Asphyxiation and Carbon Monoxide Poisoning, severe hypoglycaemia
An important event in ischemic damage is activation of glutamate receptors which causes uncontrolled entry of Ca2+ into neurons > causing further neuron death.

Question 23

What is a Subarachnoid Haemorrhage?

Answer 23

Bleeding into the subarachnoid space (between the subarachnoid & pia)

Cause of stroke from adolescence to old age

Most subarachnoid hemorrhage’s are due to a ruptured berry aneurysm.
Less common – a rupture of intracerebral hematoma.

A layer of blood is present over the subarachnoid space & therefore present in the CSF (so detectable on lumbar puncture).

Question 24

What are the 2 effects of a subarachnoid haemorrhage?

Answer 24

1 - Blood around the vessels causes vascular spasm
leads to widespread cerebral ischemia & brain swelling
2 - May be blockage of CSF reabsorption
causing acute hydrocephalus.

Question 25

What is vertebral artery dissection?

Answer 25

A relatively rare, but increasingly recognized cause of stroke
Expanding hematoma in the vessel wall
Can occur secondary to trauma or spontaneously.
large dissections can extend into the basilar artery.

Question 26

Brain Pathology from a Head Injury can be divided into 2 groups. What are they?

Answer 26

Primary
(the immediate consequence)

Secondary
(as a delayed consequence of brain swelling, bleeding, hypoxia or secondary infection)

Question 27

What is cerebral contusion (primary)?

Answer 27

Occurs when the brain moves within the cranial cavity
Causing part of the brain to be crushed by violent contact with the skull or dural membranes.
Over a period of hours, there is oozing of blood & contusions become hemorrhagic with severe brain swelling.

Question 28

What is Diffuse Traumatic Axonal Injury?

Answer 28

A result of shearing of axons due to acceleration, deceleration and torsional forces leading to severe damage to white matter tracts.
Patients with this pattern of damage who survive, will typically be severely disabled.

Question 29

What is Secondary Brain Damage – Cerebral Haemorrhage?

Answer 29

Occurs after the immediate impact
Head injury is often associated with widespread trauma
This can lead to problems maintaining blood oxygenation & blood pressure
As a consequence, head injury is often complicated by the developmend of secondary hypoxic brain damage & cerebral edema.

Tearing of blood vessels with trauma leads to 4 main types of cerebral haemorrhage:
Intracerebral hematoma, subarachnoid haemorrhage, subdural haemorrhage, extradural haemorrhage.

Question 30

What is Extradural Haemorrhage?

Answer 30

Caused by tearing of the vessels that run outside the dura.
Almost always as a result of skull fracture which tears an artery.
Most commonly middle meningeal artery (fracture of temporal bone)
The hematoma accumulates causing compression of the brain.
In many cases, high pressure arterial blood accumulates rapidly, leading to an acute decline in conscious levels with raised intracranial pressure.
In other cases, blood accumulate over a period of hours and is followed by a gradually progressive coma.

Question 31

Injury to the spinal cord is mainly caused by?

Answer 31

Due to road traffic accidents, falls & sports, horse riding accidents

Fracture & dislocation of vertebral column, causing spinal cord compression
Minor contusions can result in transient recoverable neurological abnormality
Severe contusions can damage ascending & descending tracts, as well as necrosis of the neurons in segments damaged.
Symptoms depend on location of damage. Eg. Brown- Sequard Syndrome

Question 32

True or false? Trauma to the spinal cord is a common cause of disability (younger men > women)?

Answer 32

True

Question 33

What is spinal cord compression?

Answer 33

The spinal cord & nerve roots can also be compressed due to non- traumatic causes:
Prolapse of intervertebral Disc
Osteophytes caused by spondylosis
Bone Disease (Rheumatoid or Paget’s)
Extradural tumor, abscess or meningeal fibrosis
Intradural Tumor (Schwannomma, arteriovenous malformation, meningioma)
Syringomyelia

Question 34

What is a prolapsed intervertebral disc?

Answer 34

A common cause of compression of the nerve roots
And more rarely, causes compression on the cord
The intervertebral disc contains a central nodule of semifluid matrix called the nucleus pulposus, surrounded by a ring of fibrous tissue and fibrocartilage- the annulus fibrosis.
The posterior segment of the annulus is thinner and less firmly attached to bone
After repeated unusual stress, part of the matrix of the nucleus pulposus may herniate through it.
This lesion, usually tracts posterior-laterally and compresses a nerve root in the intervertebral foramen.
Most commonly affects: L5-S1, L4-5 and L3-4

A small protrusion may produce localized pain by irritation of the posterior longitudinal ligament
A larger one may cause radiating leg pain.
The rarer central protrusions may compress the cauda equina, causing paraparesis & sphincter dysfunction.

Question 35

What is multiple sclerosis (MS)?

Answer 35

The most important demyelinating disease
Immune mediated condition, of unknown cause.
Defined by relapsing episode of immunologically mediated demyelination of the CNS.
Loss of myelin leads to failure of axonal function & neurological dysfunction.

MS lesions are confined to the brain & spinal cord
Areas of demyelination are called plaques
Best seen at the lateral ventricles, cerebellar peduncles, optic nerves & brain stem.
Areas of active recent demyelination appear as salmon- pink granular patches of softeing in white matter.
Macrophages enter the lesions and phagocytose damaged myeling, accumulating lipid and forming foam cells.
Astrocytes around plaque margins become enlarges
Remyelination may then take place in plaques, which then may be subject to further episodes of demyelination.

Areas of complete myelin loss appear as gray-pink gelatinous patches.
Axons are mostly preserved, by clear evidence of loss of axons from plaque areas
Which is a feature related to clinically progressing disability.

There is great variation in outcome.
Some only experience very minor disability and only a few episodes of demyelination.
Others, severe & frequent episodes which in later stages can progress to blindness, paraplegia, incontinence, cognitive dysfcuntion.

Question 36

What is Motor Neuron Disease (Amyotrophic Lateral Sclerosis)?

Answer 36

Causes paralysis due to death of motor neurons
Usually begins are mild weakness in one limb, which then progresses to severe paralysis
Loss of swallowing & respiration leading to death in 2- 3 years.

ALS is the most common form – loss of both cortical motor neurons & lower motor neurons in the spinal cord & brain stem

Question 37

What is Parkinson’s disease?

Answer 37

Due to a loss of neurons from the substansia nigra.
Characterized by disturbance of movement, with rigidity, slowness of voluntary movement (bradykinesis) and resting tremor.
Severity of the disease is related to loss of the neuromelanin containing nerve cells from the substantia nigra in the midbrain.
These cells normally produce dopamine.
A loss of these, reduces the amount of dopamine in the basal ganglia.
A significant proportion of patients develop dementia (Parkinson’s Disease Dementia)

Macroscopically, there is a loss of pigment from the substansia nigra
Which is due to the death of melanin containing dopaminergic cells.
The surviving cells in the substansia nigra contain spherical inclusions called Lewy Bodies – which contain the protein alpha synuclein.

Question 38

What is Alzheimer’s disease?

Answer 38

Is the most common cause of dementia
Progressive failure of memory
Degeneration of temporal and parietal association cortex
Causing dyspraxia and dysphagia & often disturbances in emotion
Death commonly due to development of pneumonia
Unknown cause – appears to have genetic link
The brain in Alzheimer’s is smaller than normal with a reduced weight
Brain slices show shrinkage of gyri & widening of sulci in cerebral hemispheres

Question 39

What is spina bifida occulta?

Answer 39

Abnormal development of the bone arch of the spinal column
Meninges & cord are normal
May be associated with sinus track to the skin surface or subcutenous lipoma.

Question 40

What is Neurofibromatosis Type 1 & 2 ?

Answer 40

NF Type 1 – Autosomal dominant disease that causes tumours of peripheral nerves
Benign tumours on peripheral nerves, called neurofibroma’s
Presence of pigmented café au lait spots

NF Type 2 – Autosomal Dominant disease that causes tumours on acoustic nerves
Development of bilateral benign tumours (called schwannoma’s) on the 8th CN aka acoustic neuroma’s
Patients present with tinnitus, deafness, meningiomas & gliomas.

Question 41

What are neuropathies?

Answer 41

Neuropathies, are diseases of peripheral nerves

They clinically manifest by sensory or motor abnormalities, which can be:
Predominantly sensory
Predominantly motor
Mixed

Question 42

What is Polyneuropathy?

Answer 42

Is generalized symmetrical involvement of peripheral nerves

Question 43

What is Mononeuropathy / Focal Peripheral Neuropathy?

Answer 43

Disease affecting peripheral nerves in a haphazard manner.
Mononeuropathy used when one nerve is affected

Question 44

What is radiculopathy?

Answer 44

Disease affecting a nerve root

Question 45

Peripheral nerves undergo 3 main types of degeneration. What are they?

Answer 45

Axonal (Wallerian) Degeneration
Distal Axonal Degeneration
Segmental Demyelination

They are capable of regeneration, however the speed at which they recover is dependant on the nature of change i.e. if the Schwann cells can remyelinate, recovery will be quicker than is Wallerian degeneration occurs.

Question 46

What is Wallerian Regeneration?

Answer 46

(Regeneration of Peripheral Nerves)

When an axon is severed or damaged, the axon & myelin distal to the injury degenerate.
The degenerate myelin & axon are removed by macrophages & Schwann Cells.
The target tissue e.g. muscle is denervated & atrophies
Shwann cells in the distal nerve proliferate and enlarge within the still in tact basement membranes tube enclosing them.
The nerve- cell body becomes swollen, the nucleus enlarges & there is an increase in the quantity of cytoplasmic intermediate filaments  this is termed central chromatolysis.
The stump of the proximal axon swells, and several small axons sprouts grow out down the column of the proliferated Schwann Cell (this acts as a guide for the regenerating axon).

The axon grows 2-3mm per day, eventually reinnervating the denervated tissue.
The axon is remyelinated, but the new myelin segments between the nodes of Ranvier, are shorter than the original nerve.

NB.
The capacity of axons for regeneration allows surgical repair of peripheral nerves by nerve anastomosis after severance. However, axons can only grown down an intact basement membrane tube of Schwann cells, not through collagenous scar.
Many sprouts may not reach the distal stump and will proliferate in the dense scar tissue to form a painful swelling called an amputation or traumatic neuroma.

Question 47

What is Distal Axonal Degeneration?

Answer 47

The ‘dying back” of distal neuropathies
These present typically with sensory loss in a “glove & stocking” distribution
Degeneration of axons occurs first
The process then extending back towards the neuronal cell body;
This in turn results in secondary loss of myelin.

Question 48

What is Segmental Demyelination?

Answer 48

Occurs when there is damage to Schwann Cells and the myelin sheath of a previously healthy myelinated nerve.
The result is an axon that shows patchy loss of internodal myelin.
During recovery, the damaged internodal myelin is usually replaced by the myelin from several adjacent Schwann cells, leading to a decrease in internodal length.
In a segment with repeated demyelination & attempted healing, there is hyperplasia of Schwann cells with concentric wrapping of their cell processes and the formation of “onion bulbs” along the nerve fibres  this is typically seen in chronic neuropathies.

Question 49

What are neuropathies caused by toxins?

Answer 49

Chronic Alcohol Abuse
Direct toxic effects of alcohol as well a the effect of vitamin deficiency

Exposure to Chemicals
Lead, arsenic, mercury & acrylamide.

Most toxins produce a dying back axonal neuropathy that results in symmetrical sensory / motor neuropathy with glove & stocking distribution – reflecting the loss of the ends of longer neurons.

Question 50

What are neuropathies caused by vitamin deficiencies?

Answer 50

In developed countries:
Alcohol abuse is the most common cause for vitamin deficiency
Followed by malabsorption from GI tract disease

Vitamin B1 (thiamine)
Most commonly associated with alcohol misuse

Vitamin B12
B12 deficiency affects haematopoietic tissue, epithelial surfaces & the nervous system.

Question 51

What is Diabetic Polyneuropathy?

Answer 51

Sensory & autonomic neuropathy is due mainly to a combination of axonal degeneration and segmental demyelination.

Motor neuropathy and cranial mononeuroathy are caused by vascular disease in blood vessels supplying nerves.

Question 52

What is vascular disease?

Answer 52

A common Cause of Peripheral Neuropathy

Vascular disease results in focal necrosis of major nerve trunks and loss of myelinated axons.

Most common cause of vascular damage to nerves are atherosclerosis & arterioscleroris
Which particularly affect arteries supplying nerves in the lower limbs
This is most common in patients with diabetes!