Neurotrauma and Neurodegeneration

Question 1

Describe Neuronal Chromatolysis

Answer 1

1. Neuronal chromatolysis:
   - Reparative response of neurons following damage to the axons
   - Neuronal body swells due to the accumulation of neurofilaments
   - There is peripheral migration of the Nissl substance to the nucleus and cell periphery
   - Neurons shink away from ECM and the space fills with fluid, these fluid filled spaces coalesce and form an avascular fluid filled cyst

Question 2

What are the pathological sequelae following axonal damage:

Answer 2

1. Proximal accumulation of beta-amyloid precursor protein
2. Axonal varicosities
3. Axonal swelings
4. Microgliosis
5. Loss of myelinated fibres
   - occurs away from the epicentre of the injury site

Question 3

What is microgliosis?

Answer 3

• The microglial response to injury
• The microglia are activated to phagocytose cellular debri (supplemented by monocytes from the blood)
• These microglial become vacuolated by accumulated lipid from the dead neurons, forming foam cells

Question 4

Describe the process of gliosis:

Answer 4

1. Following neuronal cell death and their removal by phagocytes (microglia) the astrocytes become activated
2. The activated astrocytes proliferate and form copious amounts of CSPG
3. The CSPG forms a glial scar
4. The glial scar provides strength and contracts the injury site, however it cannot be repaired (cannot be penetrated by axons or neural progenitor cells)

Question 5

What is raised intracranial pressure?

Answer 5

• Most commonly caused by bleeding in and the brain , swelling associated with cerebral infarction, growth of brain tumours
• Cerebral oedema is the accumulation of tissue fluid between the cells of the nervous system
• Symptoms include: headaches, vomiting (especially in the morning), papilledema and later epileptic seizures and coma
• If severe intracranial pressure is not allleviated the brain may hernaite through the foramen magnum

Question 6

What is non-missile vs missile trauma?

Answer 6

Non-missile (closed head injury):

• Acceleration/deceleration forces
• Rotational and shearing forces on the brain
• More common

Missile Trauma (open head injury): 
- Penetration of skull/brain by an external object e.g. a bullet

Question 7

What is the difference between primary and secondary trauma to the CNS?

Answer 7

Primary Damage:

• Occurs immediately
• Scalp laceration/fracture
• Cerebral contusions and lalcerations
• Intracranial haemorrhage
  e. g. coup lesions and countercoup lesions
  e. g. diffuse axonal injury

Secondary Damage:

• Delayed, occurs after immediate trauma
• Mechanisms damage other cells in the CNS (may be distal to injury)
• Ischemia
• Hypoxia
• Cerebral swelling
• Infection
• Due to shearing and tearing of blood vessels in the brain

Question 8

Describe coup and countercoup lesions

Answer 8

• Type of primary brain damage
  1. Coup lesions: part of the brain is crushed by violent contact with skull or dural membranes adjacent to the site of injury
  2. Countercoup lesions: occurr diagnonally opposite coup lesions as a result of the brain recoiling and colliding iwth the other side of the skull
• Severe contusions may be associated with extensive intracerebral, subarachnoid or subdural haemorrhage
• Contusions heal by gliosis

Question 9

Describe diffuse axonal injury

Answer 9

• Type of primary brain damage
• Shearing of axons due to acceleration, deceleration and torsion forces causing severe damage in the white matter tracts
• Causes widespread and extensive injury

Question 10

Describe secondary brain damage:

Answer 10

• Occurs after immediate impact and is due to shearing and tearing of the blood vessels in the brain which leads to secondary hypoxic brain damage and cerebral oedema
• Can be caused by 4 different types of intracranial haemorrhage:
  1. Extradural
  2. Subdurall
  3. Subarachnoid
  4. Intracerebral

Question 11

Describe epidural/extradural hematomas:

Answer 11

• Bleeding between the dura mater (outer membrane of the brain) and the cranium
• Usually caused by trauma to the temporal region of the skull, or a skull fracture causing the rupture of the middle meningeal artery or one of its branches
• Causes immediate concussion followed by regaining of consciousness (lucid interval), after which the patient becomes progressive comatose
• Causes death if untreated

Question 12

Describe subdural hemorrhages:

Answer 12

• Bleeding between the dura mater and arachnoid mater
• Can be acute or chronic:
  1. Acute: rupture of cortica veins in subdural space resulting in intracranial pressure increase, brain herniation, coma and death
  2. Chronic: tearing of the briding cerebral veins caused by falls or birth trauma
• Symptoms are greatly delayed (due to tearing of veins), manifests as headache, increasing drowsiness, hemiparesis and seizures
• Brain herniation and death occur in most cases

Question 13

Describe subarachnoid haemorrhages:

Answer 13

• Bleeding between the arachnoid mata and brain tissue
• Rarely due to injuries, mostly due to pathology of the brain vasculature including:
  1. Brain aneurysms (mainly congenital berry aneurysms)
  2. Subarachnoid and intracerebral hemorrhages
• Brain infarcts (most common)
• Symptoms: focal signs, transient headache and neck stiffness, sudden severe occipital headache and vomiting
• Very poor prognosis

Question 14

Describe intracerebral haemorrhages:

Answer 14

• Bleeding from within the brain parenchyma- commonly the lenticulostriate branch of the middle cerebral artery
• Most commonly the result of cerebrovascular accidents such as hypertensive vascular damage (arterioscleoris) and small microaneurysms
• Symptoms include: following physical or emotional exertion, intense headache and vomiting and rapid loos of consciousness with congested face and laboured breathing
• Prognosis is grave, with affected region of the brain becoming a cystic space

Question 15

What is a spinal cord injury? What are the two kinds?

Answer 15

• Spinal cord injuries involve the rupture or contusion of the spinal canal
• They can be traumatic e.g. car accidents or non-traumatic e.g. tumours

Question 16

What secondary pathological mechanisms occur after a spinal cord injury?

Answer 16

1. Oligodendrocyte apoptosis
2. Axonal degeneration (both superior and posterior to the injury site)
3. Gliosis (activation of microglia and astrocytes)- formation of glial scar
   - A cystic space known as a saringomyelia may form
4. Motor cortex neuronal cell death (occurs years after injury to axons)

Question 17

What are the most common pathological features of neurodegenerative diseases:

Answer 17

1. Loss of neurons
2. Variable glial and microgial activation (inflammation surrounding damaged neurons)
3. Disorders of proteostais- cellular inclusions and extracellular protein accumulations

Question 18

Describe Alzheimers Disease. its aetiology, molecular pathology, histology and gross pathology and symptoms:

Answer 18

Alzheimers disease: the most common form of dementia in the elderly

Aetiology: most cases sporadic, some involve mutations in APP gene and ApoE (E4 allele), linked to older age

Molecular pathology:

1. Formation of extracellular neocortical neuritic plaques containing deposits of B-amyeloid protein, dystrophic neurites, microglia and reactive astrocytes
2. Formation of intracellular neurofibrillary tangles, composed of hyperphosphoryated tau that appears as long pink filaments in neuronal cytoplasm

Gross pathology:

• Severe atrophy of the brain: primarily in the frontal, temporal and parietal regions
• Thinning of the gyri and prominent sulci

Symptoms:

• Impairment of higher intellectual functions
• Progressive disorientation, loss of memory, language disorders
• Over 5-10 years patient becomes mute and immobile and eventually dies (definitive diagnosis from neuritic plaques only possible at death)

Question 19

Describe frontotemporal dementia, its histopathology, gross pathology and symptoms:

Answer 19

Frontotemporal dementia (Pick disease):

• Form of dementia caused by early frontal and temporal lobe degeneration
• Type of tauopathy

Histopathology:

• Accumulation of tau protein in intracellular Pick bodies
• Active gliosis (inflammation)

Gross Pathology:
- Atrophy of frontal and temporal lobes

Symptoms:

• loss of executive function , dis-inhibition, loss of manners and inability to plan or understand consequences of actions
• causes death 3-10 years after disease onset

Question 20

Describe Dementia with Lewy Bodies, its histopatholoy, gross pathology and symptoms:

Answer 20

Histology:

• Presence of Lewy bodies (made up of a-synuclein protein) within cortical neurons (mainly seen in deeper layers of temportal and frontal cortex)
• These Lewy bodies are ill-defined pink, cytoplasmic inclusions

Gross pathology:
- Thinning of gyri in frontal and temporal lobes (but less pronounced than AD)

Symptoms:
- Similar to AD, but also with visual hallucinations, fluctuations in cognition and Parkinsonian motor symptoms (bradykinesia and rigidity)

Question 21

Describe Parkinsons Disease, its histopathology, gross pathology and risk factors

Answer 21

Parkinsons Disease:
- PD is caused by idiopathic destruction of dopaminergic neurons in the substantia nigra (part of brain that initiates body movement)

Histopathology:

• Lewy bodies seen in remaining neurons in substantia nigra, these are rounded, pink-staining inclusions with a pale halo
• The Lewy bodies stain positive for a-synuclein

Gross pathology:
- Loss of pigmentation in substantia nigra

Symptoms:
- Freezing of gait, tremor and stiffness, bradykinesia, muscular weakness

Question 22

Describe motor neuron disease (ALS), its epidemiology, pathology and symptoms:

Answer 22

Motor neuron disease:

• Diseases involving paralysis due to death of motor neurons
• Most common pattern is ALS which is the loss of upper and lower motor neurons in the brain stem and spinal cord

Epidemiology:

• Very rare
• Peaks in incidence in 5th decade of life
• Appoximately 5% of cases familial
• 2:1 male to female predominance

Pathology:

• Loss of ventral horn motor neurons and motor nuclei in brain stem
• Loss of upper motor neurons in motor cortex
• Loss of lateral and ventral corticospinal tracts
• Secondary demylination
• Mild gliosis