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 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
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
Describe penumbra in ischemic stroke
- Ischemic stroke occurs, brain tissue dies at the region of occlusion ‘infarct’
- Penumbra = tissue area surrounding an ischemic event such as thrombotic or embolicstroke gets injured
- Immediately following the event, blood flow and therefore oxygen transport is reduced locally, leading to hypoxia of the cells near the location of the original insult
- Penumbra succumbs to cell death, the infarct grows and spreads
Describe the histology of ischemic strokes
- At first, injured neurons shrink and become eosinophilic
- Neuronal nuclei condense
- Red neurons: Shrunken eosinophilic neurons (anoxic neuron) - Damaged neurons disintegrate and are removed by macrophages -> cortical atrophy and gliosisdevelop
Describe the ischemic cascade
- Energy depletion
- Failure of Na+and K+pumps
- Depolarizationof the neuronal membrane
- Neurons releaseglutamateinto synaptic cleft -> excitotoxin
- Glutamate acts on channel receptors (NMDA, AMPA) -> more Ca2+influx
- Activation ofcatabolic enzymes(proteases, phospholipases, endonucleases )
- Activation of Nitric Oxide (NO) synthase -> formation of free radicals - Free radicals and activated catabolic enzymes destroy structural proteins and DNA -> neuronal necrosis
- Free radicals injure mitochondria -> apoptosis
Chain reaction of biochemical pathways occur successively/simultaneously -> neuronal cell death
What are gliomas?
Gliomas = Brain and Spinal Tumors
- Gliomas account for 50% of all brain tumors
- Arise from the glial group of cells(supporting cells)
- Types include Astrocytoma, Ependymoma & Oligodendroglioma, Glioblastoma
- Usually highly malignant
- Affect more men than women
What are meningiomas?
- Meningiomas most frequently occurring non-glial tumors
- Arise from arachnoidal cells
- Typically slow-growing tumor forming from meninges
- Primarily affecting adults around 50 years old
- They are non-aggressive
- Occur about twice as often in women as in men
- About 80% can be surgically removed
- Interfere with circulation of the CSF causing a hydrocephalus
