Day 10 (2): Basic Pathology of Glaucoma Flashcards
What is Glaucoma?
Group of ocular diseases with VARIABLE etiologies, all causing a characteristic OPTIC NEUROPATHY
Cause: Variable
Result: Progressive degeneration of retinal ganglion cells –> CUPPING or excavation of the optic nerve head with corresponding vision loss
How is glaucoma diagnosed and classified?
Diagnosed based on: Posterior Pole pathology - glaucomatous damage to the optic nerve head
Classified based on: Anterior Pole pathology
1. Primary: Idiopathic
- Primary Angle CLOSURE Glaucoma (PACG)
- Primary OPEN Angle Glaucoma (POAG)
- Secondary: WITH identifiable cause
- Angle CLOSURE Glaucoma (ACG)
- OPEN Angle Glaucoma (OAG)
What is the lamina cribrosa?
- fenestrated, mesh-like structure consisting of a 3D network of load-bearing trabeculae that fills the posterior scleral foramen
- provides structural support to the optic nerve head and the retinal ganglion cell axons or nerve fibers that pass through its perforations
- weakest portion of the optic nerve
Normal LC:
- regularly arranged sheets
- uniformly sized pores
Pathologic LC:
- (+) bending of sheets
- irregular pore sizes
What causes glaucomatous optic neuropathy?
Exact cause remain UNKNOWN.
Prerequisite:
INHERENT susceptibility of the ONH
- genetic factors
Aggravating factors:
1. Abnormal IOP
- can occur even with normal IOP
- different individuals have different susceptibilities to different IOP levels
- Ischemia secondary to vascular dysregulation in the blood supply to the optic nerve
What are the clinical changes associated with glaucoma?
- Thinning or loss of retinal NFL
- FFA: HYPOreflective areas of RNFL drop-out or absence of white streaks on the surface of the retina following the NFL configuration
- OCT: decreased RNFL thickness
- NFL are arranged in an arcuate manner, respecting the horizontal raphe and appearing like a spade on its sides
- leads to ganglion cell apoptosis - Thinning of the neuroretinal rim
- do NOT rely on the pallor of the optic cup
- pallor (optic CUP) size changes with the size of the ONH (optic DISC/posterior scleral foramen) though the NUMBER of AXONS is similar in everyone (~ 1.5 million)
- IO: kinking or bending of vessels at the rim or vessels become farther apart - Increased excavation in the ONH surface
- shallow depression –> cupping
- ON at the level of the lamina cribrosa: most susceptible part of the ON to damage
- PATHOGNOMONIC sign of glaucoma
- IO: optic cup enlargement (higher C:D ratio)
- OCT: bean-pot excavation - Thinning and posterior bowing of the LC
- NOT seen in other causes of optic neuropathy
- due to collapse of the lamina cribrosa
+ NAION: (+) thinning of RNFL BUT (-) posterior bowing of lamina cribrosa
What histologic findings are seen in retinal ganglion cells in glaucoma?
- Destruction of ganglion cell axons (RNFL)
- level of the lamina cribrosa
- structural changes precede functional defects
- up to 50% of ON fibers lost before visual field defects develop
- axons located PERIPHERALLY in the nerve fascicle are destroyed earlier than centrally-located ones - Cystic degeneration of the ganglion cells
- causes:
+ disruption of the axonal transport of neurotrophic factors from the LGN to the ganglion cells
+ excitotoxic injury due to ischemia
- activation of apoptotic genes –> increased glutamate, Ca and Na –> increased endonucleases, proteases, NO and ROS
–> apoptosis and phagocytosis of ganglion cells
- occurs earlier in the SUPERIOR and INFERIOR poles of the ON due to: - bigger pores
- larger concentration of M cells and P cells with the largest axons
- begins in the MIDPERIPHERY and progressing CENTRIPETALLY (inwards) - Shrinkage and atrophy of the LGN target relay neurons
What histologic findings are seen in the lamina cribrosa in glaucoma?
- Alterations in the lamina cribrosa suggested to be the primary event in glaucoma
- Posterior displacement of the lamina cribrosa
- occurs first in the peripheral margins
- corresponds to regions of early axonal loss
- structure reflects the balance between IOP (outward force) and ICP (inward force)
- increasing IOP overcomes lower ICP causing the LC to bow posteriorly - Increased cupping or depth
- Focal lamina cribrosa defects (holes, disinsertions)
Discuss the molecular events in glaucoma that lead to synapse loss.
Injury –> Disrupted Ca homeostasis –> Elevated intracellular Ca levels –>
- Oxidative stress –> mitochondrial dysfunction –>
- Calpain activation –> cytoskeletal degradation –>
Effect:
1. Transport failure
2. Dendritic pruning
3. Axonopathy
End-point: Synapse Loss
What are the early changes to the optic nerve seen in glaucoma?
Earliest and most dominant responses:
- present in all stages of the disease
- creates an inhospitable environment for neuron growth
- Reactivation and hyperplasia of type 1B astrocytes
- induced by TGF-Beta
- similar to an abnormal wound healing response
- causes increased synthesis of:
+ collagen types 4 and 6
+ deformed (curled) elastin
+ tenascin: ECM component - Degenerative remodelling of LC ECM
- loss of pre-laminar astrocytic columns
- astrocyte migration into nerve fibers
- decrease in total collagen
- becomes stiff and less compliant
Succeeding changes:
- Distortion and enlargement of LC pores leading to laminar ectasia
- due to stretching and eventual rupture of connective tissue beams - Stretching and collapse of the laminar sheets
- causes compression of passing axons leading to ischemia and axonopathy
- axons swell due to accumulation of membranous vesicles leading to cystic degeneration of ganglion cells - Posterior/outward displacement of the lamina cribrosa
- earliest in SUPERIOR and INFERIOR poles
Remember: NO signs of inflammation, scarring or microglial involvement
What are the advanced changes to the optic nerve seen in glaucoma?
- Thinning of the pre-laminar ON
- due to destruction of RNFL and apoptosis of the ganglion cells
- clinical: thinner neuroretinal rim and expanding optic cup - Glial cell hyperplasia
- purpose:
+ fill-in spaces previously occupied by axons
+ phagocytose cell debris
+ produce GAGs as space-fillers - Progressive compression and flattening of the lamina cribrosa
- Excavation of the ONH surface
- “bean-pot”-shaped
- may extend beyond the choroid - Marked loss of elastic leading to stiff lamina
Discuss the different patterns of optic nerve involvement in glaucoma.
- Diffuse/Generalized Depression
- damage uniformly distributed over the ON surface
- NOT specific to glaucoma
- more common in higher IOPs and younger patients
- signs:
+ symmetric thinning of neuroretinal rim
+ later onset of visual field defects
+ generalized depression of visual field
+ likely to have abnormal psychophysical testing: color vision, contrast sensitivity - Focal/Localized Depression
- damage localized to specific region of the ON
- more specific to glaucoma
- usually due to a vascular insufficiency or dysregulation
- more common in normal to slightly elevated IOP and older patients
- signs:
+ vertical elongation of cup
+ notching of the neuroretinal rim
+ earlier onset of visual field defects
+ less likely to have color vision or contrast sensitivity issues
Most common visual field defect in focal optic nerve damage from glaucoma?
- Paracentral scotoma
- Nasal step
What are the different theories to the cause of glaucomatous optic neuropathy?
- Mechanical: abnormal IOP level
- Vascular: hypoxia from ischemia
- Biochemical: oxidative stress
- Biomechanical: mechanical stress
Remember:
- NOT mutually exclusive
- NO favored theory
Discuss the Mechanical Theory of glaucomatous optic neuropathy.
Cause: Abnormal IOP level
- causes mechanical stress and strain on the
optic nerve and the lamina cribrosa
- creates a centrifugal or outward force that:
1. compresses the laminar sheets
2. stretches and enlarges the laminar pores
3. deforms lamina cribrosa posteriorly
- with continued increase in IOP, the scleral foramen also expands, pulling the LC taut and inward
- the repetitive inward-backward (shearing) displacement of the LC causes weakening of its structure by ECM remodelling
- gradual collapse of the LC will compress the axons and disrupt retrograde axonal transport of neurotrophic factors from the LGN to the RGCs causing apoptosis
- marked decrease in the elastin leads to LC stiffness and permanent deformation
Regions with highest strain:
1. pre-laminar tissues near the scleral foramen: direct exposure to IOP
2. post-laminar tissues near the LC insertion into the sclera: most stretched
Remember:
* 1 mmHg increase in IOP equals
–> 1.6 um ONH surface displacement
–> 2.0 um anterior laminar displacement
- older age: less displacement
- Even if IOP decreased to safe levels, axon degeneration can still continue.
Discuss the Vascular Theory of glaucomatous optic neuropathy.
Cause: Hypoxia from impaired ONH microcirculation
1. Primary systemic vascular dysregulation
- seen in normal tension glaucoma
2. Elevated IOP
- compression of intraocular vessels
Pathophysiology:
- cause decreased perfusion pressure and blood flow to the lamina cribrosa
- deprives the RNF and GC of the nutrients and oxygen to properly function
- formation of reactive oxygen species:
1. Superoxide
2. Peroxynitrate: formed from fusion of NO with oxygen by activation of surrounding astrocytes
- resultant oxidative damage induces apoptosis of GC and LGN cells, causing impaired axonal transport
Risk factors:
1. Anemia
2. Diabetes Mellitus
3. Migraine
Affected vessels:
1. Short Posterior Ciliary Arteries
2. Central Retinal Artery
Presentation: splinter or flame-shaped hemorrhages
- recurrent acute focal ischemia on top of chronic
Evidence against:
1. NO direct evidence of vascular abnormality
2. Laminar blood flow is CONSTANT despite increased IOP
3. Hypotensive patients do NOT show progressive visual field loss
4. Filling defects in the FFA may be the RESULT of tissue loss and NOT the cause
5. Hemorrhages may be due to tissue loss or vessel stretching.
Discuss the Biochemical Theory of glaucomatous optic neuropathy.
Cause: Oxidative stress
Glial cells
- activated by increased IOP
- release neurotoxic factors:
1. Nitric Oxide
2. TNF-Alpha
Effects: Apoptosis of ganglion cells
1. Loss of neurotrophin action on GCs
- due to blockage of retrograde axonal transport from the LGN
2. Excitotoxic damage
- due to increased glutamate, NO, ROS
3. Oxidative damage
- pronounced with aging
4. Glial cell activation and gliosis
- divide to fill spaces left by apoptotic GCs
- associated with increased ECM production
Discuss the Biomechanical Theory of glaucomatous optic neuropathy.
Cause: Biomechanical stress on the TM, ONH and GC
- mechanosensitive cells
- induce changes to the ECM and cell cytoskeleton via undiscovered molecular mechanisms
What factors affect the individual susceptibility of patients to glaucoma development?
- Ocular anatomy
- Tissue composition and biomechanics
- ONH blood flow
- Cellular reactivity
- IOP and perfusion pressure fluctuations
What variables affect the translaminar pressure gradient?
- Intracranial pressure
- Intraocular pressure
- Lamina cribrosa composition and biomechanics
What is Open Angle Glaucoma?
- increased resistance to aqueous outflow through the trabecular meshwork
- IOP increases despite OPEN ACA
- gonioscopy: (+) posterior PIGMENTED TM
Levels of Obstruction:
- PRE-trabecular: Anterior Chamber or TM entrance
- TRABECULAR: within TM tissues
- POST-trabecular: Schlemm’s canal to episcleral veins
What are the pre-trabecular causes of open angle glaucoma?
Cause: AC anatomic abnormalities or membrane overgrowth blocking the TM
- Developmental anomalies: anterior chamber dysgenesis
- Fibrovascular membrane: Neovascular Glaucoma
- Endothelium-derived membrane:
- Iridocorneal Endothelial Syndrome
- Posterior Polymorphous Dystrophy
- Trauma or burns - Epithelial downgrowth
- Fibrous ingrowth
- Inflammatory membranes
- Fuch’s Heterochromic Iridocyclitis
- Luetic/Syphilitic Interstitial Keratitis
