Neuropathology Flashcards
Describe the anatomy of the PNS
Peripheral Nervous System: Nerves, ganglia, neuronal cell bodies and nerve endings
Ascending tracts: sensory information
Descending tracts: muscle action
Anatomy of peripheral nerves:
- Nerve: many nerve fibres
- Schwann cells
Describe the histology of nerve cells
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What are the different types of nerve and axonal injuries?
- Neurapraxia (compressed)
- Axonal Degeneration
- Axonotmesis (sheath loss)
- Neurotmesis (disconnection)
Describe neurapraxia (compressed)
- Injury to a myelinated nerve by pressure that interrupts conduction -> causing 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, i.e. a hard blow to the neck, shoulders, or back (contact sports) -> fairly common
- Endoneurium intact, axon intact –> no nerve degradation
Describe axonal degeneration
- Insults that directly injure the axon leading to axon transection/crushing leads to Wallerian degeneration
- Distal portion of the axon degenerates -> axonal degeneration is actively induced by an axon death program distinct from apoptosis -> controlled event leading to distal axon death, preventing neuronal death and promoting nerve regeneration
- Sensory or motor axons cannot effectively communicate between the periphery and the CNS
Describe axonotmesis (sheath loss)
- Nerve injury where axons and their myelin sheath are damaged, but endoneurium, perineurium and epineurium remain intact
- Mainly follows a stretch injury i.e. limb fractures and dislocations can severe peripheral nerves
- Break down of axon at distal end -> Wallerian degeneration - Optimal circumstances for regeneration
- Functional recovery possible
Describe neurotmesis (disconnection)
- Nerve injury involving complete severance or crushing of nerve
- Different degrees of severity, dependant if Endomysium, Perimysium or Epimysium are affected additionally to axonal and myelin injury - mostly spontaneous recovery not expected
- In all forms - distal end will undergo Wallerian degeneration
What happens after axonal injury ?
Hint: Wallerian Degeneration
Wallerian degeneration:
- Injury leading to axotomy
- Destruction of axon away form cell body -> swelling and subsequent granulation (takes about 3 - 4 days)
- Myelin degenerates simultaneously with the axons
- Infiltration by macrophages
- Macrophages and Schwann cells clear the debris from the axon degeneration
- Macrophages release mitogens stimulating Schwann cells to divide
- Schwann cells align in Büngner bands and express surface molecules that guide regenerating fibres
- Axons sprout at ends and reconnect & remyelination
Describe regeneration in the PNS
- Most CNS fibres cannot regenerate!
- If cell soma (region of the neuron containing the nucleus) is damaged, peripheral nerve cannot regenerate
- If axon is damaged, cell can regenerate
What are peripheral neuropathies?
- Heterogeneous group of diseases and result from inflammatory, toxic and metabolic conditions in addition to genetic defects
- Symptoms vary depending on the type of nerves affected -> movement impairment, sensory impairment, autonomic nerve impairment (control of organs)
> 100 types of peripheral neuropathy identified
- Trauma: Car accidents, sports injuries
- Diabetic neuropathy
- Chemotherapy induced peripheral neurotoxicity
- Viruses
- Autoimmune: Guillian-Barre Syndrome
- Genetic: Charcot-Marie-Tooth disease
What is Guillian-Barre Syndrom?
- Acute peripheral neuropathy = acute PNS nerve damage (caused by inflammatory, toxic and metabolic conditions in addition to genetic defects)
- Rare: 1-2 per 100,000 people
- Can be life-threatening during acute phase (~ 15% developing weakness of the breathing muscles)
- Autoimmune disease (either directed against myelin or the axon)
- Antibodies and lymphocytes attack & damage peripheral nerves
- Symptoms appear suddenly, progress rapidly, and resolve slowly as damaged nerves heal
- Cause unknown but usually follows a viral or bacterial infection (EBV, CMV, HIV, C. jejuni)
What is Charcot-Marie-Tooth disease Type 1A?
- Chronic peripheral neuropathy
- Affects ~1:2,500 people
- Many chronic neuropathies worsen over time
- Symptoms begin subtly and progress slowly
- 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 of, or mutation in, the gene encoding peripheral myelin protein-PMP22 -> hereditary neuropathy
Describe trauma to the CNS and list the different types
Trauma: Injury or damage to living CNS Tissue caused by an extrinsic agent or force by either direct or indirect mechanisms
Diffuse Traumatic Brain Injury:
- Generalized injury to all regions of the brain
- Diffuse Traumatic Axonal Injury
- Diffuse Hypoxic Injury
Focal Traumatic Brain Injury
:
- Localized injury of the brain
- Lobar cerebral contusion
- Subdural hemorrhage
Describe diffuse traumatic brain injuries (TBI) and the two types
- Generalised injury to all regions of the brain
- Occurs when an outside mechanical force is applied to the
- Brain can become injured whether or not the skull is fractured
- Negatively impacts brain functioning
The most common causes of TBI:
- Falls (28%)
- Motor-vehicle traffic crashes (20%)
- Being struck by or against an object (19%)
- Assaults (11%)
- Blasts (active duty military personnel in war zones) (high)
Primary brain injury (mechanical damage):
- Cerebral contusions
- Lacerations
- Diffuse axonal injury
- Hemorrhage (sometimes considered secondary)
Secondary injury to brain tissue (indirect result):
- Intracranial hypertension
- Brain shift and herniation
- Biochemical processes
- Swelling
- Cerebral ischemia
Provide two examples of diffuse traumatic brain injuries
Diffuse Traumatic Axonal Injury
(primary)
- Caused by global disruption of axons due to severe shearing forces
Results in:
- Immediate primary axotomy
- Delayed secondary axotomy principally due to ischemia
- Example: severe blunt force impacts in any direction
- Immediate loss of consciousness following impact
- No lucid interval
- Sustained unconsciousness and vegetative state until death
- Focal axonal injury may occur in milder forms with recovery of consciousness
Diffuse Hypoxic Injury (secondary/indirect)
Describe focal traumatic brain injuries and list the different types
Localised injury of the brain
- Lobar Cerebral contusion
- Brain hematomas/hemorrhages (Epidural/Subdural hematomas)
Describe lobar cerebral contusion?
- Results from “blow to the head” = blunt trauma
- Caused by rapid tissue displacement
- Bruising of brain parenchyma is more serious than a concussion
- Occurs when brain contacts rough skull surfaces such as orbital floor and petrous ridges
- Rapture of vessels -> hemorrhage, tissue injury, edema
- Clinical symptoms: Drowsiness, confusion, agitation, hemiparesis, unequal pupil size
Describe brain hematomas/hemorrhages and the different types
- Brain trauma often results in hemorrhaging from a ruptured vein or artery
- Skull does not allow for expansion and pressure forces brain toward open space (foramen magnum)
- Headaches, agitation, drowsiness
- Can result in major consequences & death if not treated quickly
Epidural Hematoma:
- Have highest mortality rate of the hematomas
- Between skull and dura mater
- Even when treated quickly mortality rate is 30%
- Results from a torn artery and its branches
- Increased intracranial pressure
Subdural Hematoma:
- Occur more slowly because it is a venous hemorrhage
- Between the dura mater & arachnoid meningeal layers
- Caused by blunt trauma to frontal or occipital lobes and can tear subdural veins
- Pushes brain away from skull across midline (including ventricles)
Whats the difference between epidural and subdural hematomas?
What is the histology of diffuse axonal injury?
- 4-5 hours: Focal accumulations of β-amyloid precursor protein (APP)
- 12-24 hours: Axonal varicosities/swellings
- 24 hours - 2 months: Axonal swellings
- 2 weeks - 5 months: Micro-gliosis
- 2 months – years: Loss of myelinated fibres
Describe neurodegenerative disease and the pathological hallmarks of neurodegenerative disease
Neurodegenerative diseases are characterized by the progressive loss of neurons, typically affecting groups of neurons with functional interconnections
Hallmarks:
- pathological protein aggregation
- spreading of protein aggregates to healthy neurons
- activation of the innate immune system
- Neuroimmune alterations (synaptic and neuronal network dysfunction)
- Oxidative and ER stress
- Metabolic dysfunction (altered energy homeostasis)
- aberrant proteostasis (protein homeostasis)
- cytoskeletal abnormalities
- DNA and RNA defects
- inflammation
- neuronal cell death
Explain the pathological hallmarks of neurodegenerative disease using Parkinson’s Disease as an example
Parkinson’s Disease:
- Atrophy & loss of dopaminergic neurons in substantia nigra pars compacta (SNPc) in basal ganglia
- Depigmentation of the substantia nigra in PD
- Loss of dopamine in deep structures has profound effects (resting tremor, Bradykinesia, rigidity, postural imbalance)
Histology:
- Accumulation of intracellular fibrillar aggregates = Lewy bodies (mutant α-synuclein forms fibrils together with ubiquitin and neurofilaments)
- Medium age of onset 60 years old
- 95% are sporadic, 5% genetic cause
Describe strokes and the different types
Stroke:
- Clinical symptom of cerebrovascular diseases
- Either a transient or permanent reduction to cerebral blood flow
Two types:
- Haemorrhagic
- Ischaemic
(majority of cases, more responsive to treatment)
What are hemorrhagic strokes?
Occurs from rupture of weakened blood vessel:
- Typically weakened from atherosclerosis from hypertension
- Weakened blood vessels can lead to aneurysms
- Sudden and often lethal
- Most common cause is uncontrolled hypertension
- Most occur in the cerebrum and bleed into lateral ventricle
- Often preceded by an intense headache and vomiting
- Prognosis is poor
Two types:
- Subarachnoid
- Intracerebral
