CNS Pathology

Question 1

Provide an overview of PNS and CNS disorders

Answer 1

• PNS: Axonal injury and neuropathies
• CNS: Trauma, demyelinating disorders, neurodegenerative disorders, neoplasia, infectious disorders and CV related stress

Question 2

What is the PNS and structures involved

Answer 2

• Structures: Nerves, ganglia, neuronal cell bodies and nerve endings, ascending tracts (sensory information) and descending tracts (muscle action)
• Peripheral Nerves: Epineurium surrounds nerve, perineurium surrounds fascicles, endoneurium surrounds peripheral (myelinated) nerve fibre, myelin sheath formed by schwann cells surrounds axon

Question 3

List the different types of nerve injuries

Answer 3

• Neurapraxia
• Axonal degeneration
• Axonotmesis
• Neurotmesis

Question 4

What is neurapraxia

Answer 4

• Injury to a myelinated nerve by pressure that interrupts conduction
• Causes temporary paralysis and loss of function but not degeneration
• Followed by a complete and rapid recovery
• Relatively mild type of nerve injury, often result of trauma to the body
• Endoneurium intact, axon intact and no nerve degradation

Question 5

What is axonal degeneration

Answer 5

• Direct injury to axon leading to axon transection / crushing leads to Wallerian degeneration (axotomy, swelling, granulation)
• Controlled event leading to distal axon death
• Preventing neuronal death, promoting nerve regeneration
• Sensory / motor axons cannot effectively communicate between PNS and CNS

Question 6

What is axonotmesis

Answer 6

• Nerve injury where axons and myelin sheath are damaged
• Endoneurium, perineurium and epineurium remain intact
• Mainly follows a stretch injury
• Break down of axon at distal end causes Wallerian degeneration (axotomy, swelling, granulation)
• Optimal circumstances for regeneration and functional recovery possible

Question 7

What is neurotmesis

Answer 7

• Nerve injury involving complete severance or crushing of nerve
• Different degrees of severity
• Mostly spontaneous recovery not expected
• In all forms distal end will undergo Wallerian degeneration (axotomy, swelling, granulation)

Question 8

Differentiate between CNS and PNS nerve regeneration

Answer 8

• CNS: Most CNS fibres cannot regenerate
• PNS: If soma is damaged peripheral nerve cannot regenerate (cell body / nucleus) but if axon is damaged the cell can regenerate (axonal degeneration / demyelination)

Question 9

Describe the events following injury and mechanisms of repair

Answer 9

• Nerve injury and nerve will begin to degrade
• Axon surrounding myelin break down, myelin degenerates simultaneously
• Phagocytic macrophages interact with schwann cells to remove injured tissue debris
• Connection with target muscle lost, leading to muscle atrophy and fibrosis
• Axon sprouts with a fingerlike growth cone advance using schwann cells as guides (align in bungner bands and express surface molecules)
• Newly connect axon matures and the pre-injury cytoarchitecture and function are restored

Question 10

What are peripheral neuropathies and symptoms

Answer 10

• Heterogeneous group of diseases
• Result from inflammatory, toxic and metabolic conditions in addition to genetic defects
• Symptoms vary depending on the type of nerves affected
• Movement, sensory and autonomic nerve impairment (control of organs)

Question 11

What are the causes of peripheral neuropathies

Answer 11

• Altered metabolism, covalent modification
• Altered organelle function and reactive oxygen species formation
• Altered intracellular and inflammatory signalling
• Slowed axonal transport and altered ion channel dynamics and expression

Question 12

What are the types of peripheral neuropathies

Answer 12

• Trauma (car accidents, sports injuries)
• Diabetic neuropathy
• Chemotherapy induced peripheral neurotoxicity
• Viruses
• Autoimmune (Guillain-Barre Syndrome)
• Genetic (Charcot-Marie-Tooth disease)

Question 13

What is Guillain-Barre syndrome (acute peripheral)

Answer 13

• Acute peripheral neuropathy
• Demyelinating disorder
• Very rare (1:100,000)
• Can lead to death from failure of respiratory muscles within days of onset of symptoms
• Autoimmune disease (against myelin or axon)
• Antibodies and lymphocytes attack and damage peripheral nerves
• Symptoms appear suddenly, progress rapidly, and resolve slowly as damaged nerves heal
• Cause unknown, usually follows viral / bacterial infection

Question 14

What is Charcot-Marie-Tooth disease (chronic peripheral)

Answer 14

• Chronic peripheral neuropathy
• Symptoms begin subtly and progress slowly
• More common (1:2,500)
• Both motor and sensory abnormalities are common (muscle weakness & pain)
• Decreased reflexes, difficulty heel walking, calf atrophy
• Follows a chronic relapsing-remitting or progressive course
• Caused by duplication / mutation of PMP22 (peripheral myelin protein) or hereditary neuropathy

Question 15

What is trauma, a concussion and the types of trauma to the CNS

Answer 15

• Injury or damage to living CNS tissue caused by an extrinsic agent or force by either direct or indirect mechanisms
• Concussion: Traumatic brain injury that can lead to bruising, swelling, tearing of BV and injury to nerves
• Types: Diffuse and focal traumatic brain injury

Question 16

What is diffuse traumatic brain injury (DTBI)

Answer 16

• Generalised injury to all regions of the brain
• Axonal or hypoxic injury
• Negatively impacts brain functioning
• Brain can become injured whether or not the skull is fractured
• Primary (mechanical damage) and secondary (indirect result)

Question 17

What is axonal injury (DTBI)

Answer 17

• Caused by global disruption of axons due to severe shearing forces
• Immediate primary axotomy, delayed secondary axotomy principally due to ischaemia
  Pathology
• Focal accumulations of β-amyloid precursor protein (4-5h)
• Axonal varicosities / swelling (12-24h)
• Axonal swellings (24h-2m)
• Microgliosis (2w-5m)
• Loss of myelinated fibres (>2m)

Question 18

What is focal traumatic brain injury (FTBI) and cerebral contusion

Answer 18

• Localised injury of the brain
• Blunt forced trauma, rapid tissue displacement, bruising of brain parenchyma, brain contacts rough skull surfaces (orbital floor / petrous ridges)

Question 19

What is a hematoma (FTBI)

Answer 19

• Brain haemorrhaging from a ruptured vein or artery
• Increasing pressure forces brain towards foramen magnum
• Symptoms: Headaches, agitation and drowsiness, can result in death if not treated quickly

Question 20

What are the two types of hematoma’s (FTBI)

Answer 20

Epidural:
- Between skull and dura mater
- 30% mortality rate
- Torn artery increases intracranial pressure
- Rapidly expanding with arterial blood, skull fracture, torn middle meningeal artery
- Dura pushed away by hematoma
Subdural:
- Between dura matter and arachnoid meningeal layers
- Occur more slowly (venous)
- Pushes brain away from skull across midline (including ventricles)
- Dura is attached to skull, hematoma cannot cross falx cerebri, tentorium may form

Question 21

What are neurodegenerative disorders

Answer 21

• Characterised by the progressive loss of neurons, typically affecting groups of neurons with functional interconnections
• Parkinsons
• Alzheimers
• Huntingtons

Question 22

What is Parkinson disease and Lewy bodies

Answer 22

• Atrophy and loss of dopaminergic neurons in substantia nigra pars compacta (SNPc) in basal ganglia
• Depigmentation of substantia nigra
• 99% sporadic and 5% genetic causes
• Loss of dopamine
• Resting tremor, bradykinesia, rigidity, postural imbalance)
• Lewy Body: Accumulation of intracellular fibrillar aggregates

Question 23

What are cerebrovascular diseases and strokes

Answer 23

• Cerebrovascular Disease: Brain disorders caused by pathologic processes involving blood vessels
• Stroke: Acute-onset neurologic deficits resulting from hemorrhagic or obstructive vascular lesion

Question 24

What is an ischaemic stroke

Answer 24

• A clot blocks BF to an area of the brain due to occlusion
• Cause: Embolism, thrombosis of cerebral artery, hypo-perfusion
• Result: Decrease in cerebral blood flow / oxygen supply (hypoxia), widespread neuronal cell death (infarct grows and spreads), penumbra (injury of surrounding tissue)
• Histology: Eosinophilic neurons and cytoplasm, pyknosis, cortical atrophy and gliosis develop

Question 25

What is a haermorrhagic stroke

Answer 25

- Bleeding occurs inside or around the brain tissue due to rupture of blood vessels - Types: Subarachnoid and intracerebral - Cause: Rupture of a weakened blood vessel (atherosclerosis from hypertension), uncontrolled hypertension - Location: Cerebrum and bleed into the lateral ventricle - Result: Sudden and often lethal, poor prognosis

Question 26

What is the ischaemic cascade

Answer 26

- Series of biochemical reactions that are started in the brain after ischaemia takes place - Within seconds or minutes of inadequate blood supply

Question 27

List the steps involved in the ischaemic cascade

Answer 27

- Vascular occlusion decreases BF (ischaemia) leading to energy depletion - Failure of NaK pumps, depolarisation of neuronal membrane (loss of function) and AnO2 glycolysis (acidosis) - Neurons release glutamate into synaptic cleft leading to excitotoxin - Glutamate acts on channel receptors and opens NMDA and AMPA receptors leading to Ca influx - Ca influx causes activation of catabolic enzymes and NO synthase (formation of free radicals) - Free radicals and catabolic enzymes destroy structural proteins and DNA - Neuronal necrosis edema / lysis, lipid peroxidation and membrane disruption (all induce apoptosis) - Free radicals also injure mitochondria and lead to apoptosis through pro-apoptotic molecules

Question 28

What is neoplasm and neoplasia

Answer 28

- Neoplasm: Abnormal mass of tissue, growth exceeds and is uncoordinated with that of normal tissues and persists in excessive manner after cessation of stimuli - Neoplasia: Cancer, new growths of cells in the body

Question 29

What are the two types of neoplasms

Answer 29

- Glioma: Tumours that arise from the glial group of cells (supporting cells), 50% of all brain tumours, highly malignant - Meningioma: Non-glial tumours, slow growing, form from meninges, non-aggressive, interfere with circulation of CSF (hydrocephalus), 80% surgically removed

Question 30

What are infectious disorders

Answer 30

- Infections of the brain can be caused by viruses, bacteria, fungi, or, occasionally, protozoa or parasites

Question 31

What are two examples of infectious disorders

Answer 31

- Encephalitis: Infection causing inflammation of the brain, viruses are most common cause - Meningitis: Inflammation of meninges, bacterial and viral meningitis can develop into encephalitis