Pathophysiology Flashcards
The emmetropisation mechanism:
Hyperopic defocus decreases amplitude of response from retinal cells
Altered signal communication through RPE and choroid to sclera
Gene expression in scleral fibroblast altered
Scleral ECM remodelled, increasing scleral creep rate
Axial elongation > decreased hyperopic defocus
Theories for myopia development:
Dopamine theory: Decreased sun > poor activation of dopamine receptors in sclera > myopic development
Hyperopic defocus theory: peripheral hyperopic defocus (accom lag from near work) > axial elongation to resolve peripheral blur > foveal blur
Hyperopia pathophysiology:
Product of poor emmetropisation (commonly 0.5D)
Genetic factors/environment > dysfunction of signalling loop
Consequences of uncorrected hyperopia:
Anisometropia (different refractive error) > poor development of visual pathway > amblyopia
Excess accommodation > over convergence (near triad) > esophoria greater at near > strabismus / diplopia > amblyopia
Accommodation process in latent hyperopia:
Blur signal received by visual cortex > bilateral Edinger Westphal nuclei (CN3 oculomotor) in midbrain > preganglionic parasympathetic fibres move with CN3 to ciliary ganglion to synapse to postganglionic neurons > neurons travel with CNV1 ciliary nerves to ciliary muscle and pupillary sphincter muscle > activation of muscarinic receptors by Ach > contraction of ciliary muscle and sphincter muscle
Helmholtz theory of accommodation (what ciliary contraction does)
Contraction > forward movement of muscle, slacking zonules attached to lens > lens bulges naturally > increased curvature/thickness/refractive power > image focus moved forward onto retinal plane.
Convergence process in accommodation:
Blur/disparity activates supraocular motor nuclei > innervating oculomotor nuclei > axons sent to medial longitudinal fasiculus > contraction of medial rectus via CN3 > convergence while accommodating
Pupil constriction process in accommodation :
Detection of blur in visual cortex > activation of bilateral pretectal nuclei > bilateral Edinger Westphal nuclei > preganglionic parasympathetic nerves with CN3 move to ciliary ganglion > post ganglionic fibres with CNV1 to iris sphincter muscle > contraction of iris
Accomodation reflex mechanism:
Hyperopic defocus > LGN/optic radiations > visual cortex in occipital lobe >
CN3 with edinger westphal activation > ciliary ganglion > Accomodation/miosis/convergence
Presbyopia pathophysiology:
^ thickness / loss of Ant. Capsule pliability > capsule failure to mould lens
Loss of lens elasticity with constant growth (mitosis) > decreased amplitude of accommodation
Ciliary muscles undergo compensatory hypertrophy (50% stronger than at birth)
Mechanisms of cataract formation:
1: Cell proliferation/differentiation disruption (Growth factors)
2: Metabolic disturbance/osmotic regulation (Na/Ca)
3: Calpains
4: Post-translational modification (lens proteins)
5: Oxidative damage
6: Loss of defense mechanisms
Patho of nuclear cataracts:
Mechanisms 1-6
1. Na/Ca transport loss > osmotic imbalance > intracellular vacuoles/high-mol-weight aggregates
2. Calpain overactivation > disruption of crystallin structure > light scatter
3. PTM glycation of tryptophan > fluorescent chromophore > brunescence
4. Protein oxidation
5. Cortex-nucleus barrier to glutathione
Patho of cortical cataract:
Mechanisms 2/3
Dysfunctional Na/K from damage > NA/K homeostasis loss > Ca/Na influx > overhydration/ calpain activation
Crystallin proteolysis > soluble protein decrease (relative insoluble increase) > ray-like space opacify
Patho of PSC:
Mechanism 1
DM / Cort. / age > Change in GF expression (FGF) > aberrant epith. Proliferation at germinative zone
Dysfunctional cells collate with adjacent fibers forming balloon cells
Organelle retintion > Poor Na/K atpase transport > swelling > vacuoles / extracellular granular material
Growth factors in lens mitosis:
Fibroblast (FGF)
Epidermal (EGF)
Insulin-like (IGF)
Platelet-derived (PDGF)
Transforming (TGF-beta)
Disturbed cell proliferation in cataracts:
Fibroblast growth factor (FGF) stimulates proliferation/differentiation of epithelia (^FGF at equator)
Change in homeostasis of GFs / cytokine-mediated inhibition of production > opaque PSC
Post-translational modification (PTMs) in cataracts:
Additive / Subtractive / Neutral PTMs
Crystallin modifications > change in weight/conformation > thiol group exposure > oxidation > disulphide bond formation > aggregation
Metabolic disturbance in cataracts:
Altered gene expression > enzyme/GF/membrane protein dysregulation > ATP/ion transport/Ca metabolism/antioxidant dysregulation
Na/K ATPase pump loss > Na influx > water influx (^with membrane protein alteration) > swelling
Altered membrane protein > Ca influx (from ^aqueous conc.) > Ca oxylate crystals/ Ca-protein bonds/ calpain activation/ epithelia differentiation alteration
Calpains in cataracts:
Ca activated intracellular cysteine proteases
Decreased calpains > increased damaged protein levels
^Ca > excess activation > proteolysis of crystallin < precipitation of proteins < disorganization of refractive components
Additive PTMs in cataracts:
Disease: diabetes (glucose/ascorbate)/renal loss (cyanate)/aging (photo-oxidation products)/steroids (ketoimines) > methylation/acetylation/carbamylation/glycation > molecules added to lens proteins > alteration > aggregation
Polymerization > protein susceptible to photo-oxidation (UV) > modification of protein-bound tryptophan (or glycation) > presence of fluorescent chromophores > brown coloration
Neutral PTMs
Isomeration/deamidation > conformation change
Alpha-crystallin (chaperone) isomeration (time related) > loss of b/y crystallin regulation, and aggregation
Subtractive PTMs
Proteolysis/cleavage of crystallins > protein precipitate build up
Cleavage of membrane proteins (channel) > ion/glutathione transport dysregulation > vacuole formation/oxidative damage
Other types of cataracts:
Congenital (blue dot)
Trauma (Rosette)
Metabolic (myotonic dyst. > Christmas)
Disease (Uveitis > PSC)
Toxic (cort. > modified Na/K)
Loss of defence mechanisms in cataracts:
Glutathione/ascorbate (from vit.)/tocopheroles/carotenoids/antioxidant enzymes keep proteins from oxidation.
Age > nucleus-cortex glutathione barrier
Vitreous degeneration (age) / vitrectomy > ascorbate loss > nuclear cat
Systemic disorders in cataracts:
Diabetes > ^glucose > conversion to sorbitol by aldose reductase in lens > water influx > lens fiber swelling/rupture > PSC/Cortical opacity
Glycation PTM > aggregation
Sorbitol reduction > antioxidant loss > ^oxidative stress
Diabetes > snowflake cataracts
Vicious cycle:
Loss of aqueous or evaporation > hyperosmolarity > epithelial irritation > Mitogen-activated protein kinase (MAPK) & NFkB activation > inflammatory mediator release (IL-1 & TNF-1/MMPs) > Matrix metalloproteinases damage epithelium / goblet cells > epitheliopathy (corneal epithelium loss) > pain > reflex stimulation
ADDE > lack of watering > further hyperosmolarity
EDE > poor lipid layer > watering
Lipid layer:
Thin outer meibum layer from sebaceous glands in tarsal plate (Meibomian glands) secreted during blink
Prevent evapouration, acts as surfactant (spreads film)
Non-polar cholesterol, esters, phospholipids, alcohols
Oxidative damage in cataracts:
Cortex mitochondria must keep O2 conc. Low in nucleus, crystallin oxidation > high weight aggregate formation > ^RI/scatter/hardening (nuclear sclerosis)
Age* > mitochondrial function loss > ^ROS presence > ^O2/ROS in nucleus
UV filter breakdown/photosensitizer breakdown > ^ROS
Antioxidant loss > decreased O2 consumption > ^O2 exposure of proteins > ^crystallin oxidation
Age > nucleus-cortex antioxidant barrier > glutathione loss > ^nucleus generated oxidative components (H2O2)
Traumatic cataract:
Blunt (without capsule rupture) > ant./PS cataract from rapid water influx > opacity (rosette cat)
Opacity will subside if capsule is not ruptured
Heat > IR exposure > glass blowers cat
Aqueous layer Components:
Water, electrolytes, proteins, growth factors, pro-inflammatory interleukin cytokines (accumulate during sleep), Lysozyme, lactoferrin, urea, glucose, ions (Ca/Mg/Na/K), IgA
Mucin layer composition
Thinnest layer of mucus from goblet cells in conj. / plica semilunaris / glands of henle & Manz
Hydrophilic High mol. Wgt. Mucin glycoproteins (transmembrane or secretory)
Transmembrane mucins bind glycolax from corneal epith.
Secretory are soluble in aqueous forming gel
Lacrimation reflex:
Stimulation > CN5 sensation > brainstem > parasympathetic nucleus of CN7 / sympathetic of medulla > lacrimal gland / spinal cord > lacrimal gland
ADDE from secretion stimulation alteration:
Reflex hyposecretion from reflex sensory block (CLs/LASIK/herpes/diabetes) or reflex motor block (CN 7 lesion)
Blockage of para/sympathetic nerves to lacrimal gland
Decreased androgen from hormone loss (age)
Exposure to anti depressants/histamines/birth control
Eitology of DED symptoms:
Nociception from long/short ciliary of CNV1 from:
Tear breakup > exposure
Mechanical friction from lid/globe
Inflammatory mediators
Meibomian gland dysfunction causes:
Drop out (age>50)
Gland replacement (Distichiasis)
Hypersecretory glands (Seborrhea / retinoid therapy)
Gland obstruction
Glaucoma medication (pilocarpine)
BCC patho:
UV on puripotent stem cells > mutation > unregulated proliferation of abnormal basal cells
SCC patho:
UV > proliferation (^mutation) / gene alteration / immunosupression > p53 / melanocortin-1 receptor gene alteration > unregulated proliferation of squamous epith. w/o apoptosis > dermis invading tumor
SGC patho:
Idiopathic > proliferation of sebaceous gland cells > neoplasm of lipid containing cells
Malignant melanoma patho:
UV/age/genetics/freckle > Malignant tranformation of intraepidermal melanocytes > atypical melanocyte proliferation
Pingueculum patho:
UV/age > degeneration of stromal elastin/collagen
Dilator pupillae muscle:
Single layer of myopeithelium (muscle base, epith. Apex) at pupil base.
Innervated via postganglionic sympathetic fibers from sup. Cervical ganglion.
Nerves travel with long ciliary nerves of CN6
*supplied via noradrenaline
UV factors in pterygium formation:
Fibrovascular proliferation of degenerative bulbar conj. UV > several causative factors:
Endogenous photosensitiser activation > ^ROS > oxidation breaks ECM > altered collagen/elastin synthesis
^Expression of epidermal GFs > cytokine production (IL-6/8) and MMP-1
Genetic mutations (possible p53)
Pterygium patho following UV:
^pro-inflammatory cytokines (IL/TNF-a) > inflammatory influx
Epidermal GF / PDGF > cell proliferation / migration
^expression of pro-angiogenic factors (IL-6/8, VEGF, MMPs) > vascularisaion
^MMPs > ECM remodelling > Bowmans layer breakdown
Lesion invades cornea following bowmans damage
Sphincter pupillae muscle:
Circular smooth muscle at inner ring of pupil.
Innervated via post ganglionic parasympathetic fibers from ciliary ganglion.
Nerves travel with CN3 to ganglion, then with short ciliary fibers of CN6
*supplied via ACh
Afferent pupil pathway:
Retinal light input > Ganglion cell axions > optic tract > split at chiasm > split before LGN > sup. Colliculus > synapse with olivary pretectal nucleus.
Afferent (retina) / Efferent (midbrain light reflex) signals processed > ipsi/contralateral Edinger Westphal > parasympathetic path.
Parasympathetic pupil pathway:
Edinger Westphal > with CN3 (accommodative axons) > cavernous sinus > synapse at ciliary ganglion > with short ciliary via subarachnoid space > iris sphincter > bilateral / equal constriction
Sympathetic pupil pathway:
1st neuron: hypothalamus > ciliospinal Centre of bulge and Waller (C8/T2)
2nd: preganglionic fibers pass stellate ganglion (lung apex) > sup. Cervical gang. (jaw)
3rd: postganglionic fibers plexus with carotid > cavernous sinus > SO fiss. With nasociliary of CN5 > long ciliary in suprachoroidal space > dilatory > mydriasis
Also innervate mullers. facial innervation splits before sup. Cervical G.
Adies tonic pupil:
Segmental denervation of post gang. Parasym. > sphincter loss > dilation and wormlike light response
Blur in affected eye with light-near dissociation (accomodative response is healthy following aberrant regen)
Caused by viral infections, usually women
Myasthenia gravis:
Autoimmune disorder > auto antibodies against Ach receptors of striated muscle > weakness
Causes limb weakness, lack of expression, ptosis +_ diplopia worsening over the day.
Tested via 1minute upgaze, or ice pack for 2m (improves neurotransmission)
Aberrant regen:
Adies: acc. Parasym. From ciliary muscle innervate iris sphincter (2 months) > light/near dissociation > reversal of anisocoria greater in dark
CN3 palsy: accom. Parasym. Regenerate denervated pupils > miosis (anisocoria reversal). Regen can come from oculomotor fibers > miosis on different gaze
Follicles and papillae:
F: lymphocyte hyperplasia at fornix/tarsal > grey (macrophage) masses > rice grains
P: epith. Hyperplasia w/ infiltrate mast cells/eosinophils/fibroblasts > small tarsal vascular cobblestones
Functions of the conjunctiva:
Connect lids to eye (enclosed sac)
Mucin/aqueous production
Immune function (Macrophages, langerhans cells)
Mediates passive/active immunity
Structure of conjunctiva:
Epithelium: columnar W/ goblet apocrine glands and langerhan immune cells
Substantia propria: lymphoid layer (neutrophil/mast/Tcells) and fibrous layer (BV/nerves)
SAC/PAC patho:
Year long (Periennial) or seasonal allergens > type 1 immediate hypersensitivity
Allergen binds IgE on mast cells > degranulation > release of histamine (itch), prostaglandins (dilation/pain)
Vernal keratoconjuntivitis patho:
Allergen exposure usually worse in spring(vernal) > type 1 hypersensitivity
Allergen binds IgE on mast cells > degranulation > release of histamine (itch), prostaglandins (dilation/pain)
Activation of T cells > severe inflammation > diffuse papillary hypertrophy / tarantas dots
Atopic keratoconjuntivitis patho:
Allergen exposure (Px usually have many allergens) > type 1 immediate hypersensitivity with type IV delayed hypersensitivity.
IgE > degranulation > histamine/prostaglandin.
Activation/infiltration of T cells > conj. Ciatration (severe inflammation)
Giant papillary conjuntivitis patho:
Allergic or mechanical w/atopy (primary) or CLs (secondary)
Type 1 immediate HS reaction from allergens (primary) or antigen deposits on CLs (secondary)
Repeat exposure w/conj. Trauma > type IV basophil HS reaction
CL associated keratitis patho:
CLARE/CLPU > inflammation > epithelial break > vulnerable to microbial keratitis
Most commonly P.aeruginosa
Ocular defences:
Lids: physical/flushing
Tear film: IgG/A, lactoferrin, lysozyme
Cornea epith.: immunoglobins (IgG/A) defer microbe adhesion
Mucin: trap microbes
Innate immune: complement protein system
Tight junctions: prevent passage
Acanthamoeba patho:
Corneal epith. irritation > mannose glycoprotein upregulation > Acan. trophozoites adhere via acanthapodia > protease MIP133 release > epith. Cytolysis > stromal invasion / degregation
Immune neutro/macro. Influx > immune proteases > ring infiltrates
Acan. Cluster nerves > immune/anti-microbial response > form dormant cysts
Antigen-antibody immune response:
Pathogen recognition > neutrophil/machrophage influx > bacterium phagocytosis > stromal infiltrate
Bacterial proteases degrade stroma > stromal loss/scarring > corneal perforation
Fungal keratitis patho:
Adhesion following epith. Dysfunction > proteolytic enzyme release > epith. Necrosis > stromal collagen dissolution
^size > poor neutophil phagocytosis
Usually present with bacterial co-infection
HZO keratitis process:
Varicella zoster initial infection (chickenpox) > rash, flu, pneumonia
VZV moves to dorsal root and cranial nerve ganglia (retrograde transport)
Reactivation > shingles(skin) / HZO(CNV1)
GPC patho (CLs):
Allergic response type 1/4 of tarsal conj. To environment antigens adhering to mucus / proteins coating CLs
And/Or
Mechanical trauma of conj. On CKs > activation of mast cells / eosinophils / basophils > cytokine/GF recruitment > fibroblast stimulation > upregulation of collagen/ECM production > papillae formation
Microbial keratitis from CLs patho:
CL overwear/^Dk/t > epith. microtrauma > CL colonised microbe (P.aeruginosa/acanthamoeba) invasion
Protective glycolax breach > microbe migration > toxin release > antigen-antibody response
CL hypoxia patho:
Dt/k less than 87(overnight) or 24(daily) > Poor O2 diffusion > hypoxia > anaerobic metabolism > ATP decrease / lactic acid increase > pH decrease / ion pump loss > oedema / immune loss
CL neovascularisation patho:
Extended wear/sleeping in low Dk/t CLs > poor O2 diffusion > corneal hypoxia > anaerobic metabolism > ATP loss/LA increase > ion pump loss/pH decrease > immune response > growth of conj. Vessels into cornea
CL associated dry eye patho:
CL causes pre-corneal tear film instability > PCTF disruptions > tear thinning/TBUT loss > mucin increase > tear osmolarity
Poor CL hydration > CL drawing moisture from tears > dehydration
Tight lens syndrome patho:
Desiccation/steepening of soft CLs during night wear > tightening of lens > loss of lens motion > ocular surface disruption
3/9’ staining patho:
Mechanical trauma of RGP on limbal conj.
Abnormal bling > altered distribution of tears > desiccation > limbal staining
Toxic/allergic conjuntivitis from CLs patho:
Poor neutralisation of hydrogen peroxide cleaning agent > chemical toxicity
CL solution preservative absorbtion > chronic solution toxicity
Allergic response to solution preservatives > type 1 immediate / type 4 delayed hypersensitivity reaction
HSK reactivation manifestations:
- Epithelial: dendritic, geographic, metaherpetic ulcer, neurotrophic keratitis
- Stromal: stromal necrosis, immune stromal keratitis
- Endothelial: disciform/diffuse endothelitis
AC: Keratouvitis / trabeculitis
Contact lens associated acute red eye (CLARE) patho:
Gram- bacteria colonisation of CL (P.aeruginosa) > Exotoxin release > antigen-antibody immune response > inflammatory cascade > immune influx (infiltrates) / vessel dilation > sterile corneal inflammation
HSK dendritic ulcer:
Reactivation > anterograde migration via CNV1 > active viral replication in corneal epithelium
Swollen opaque epith. Cells > punctate keratitis > Desquamation of central cells
Dendritic progression via virus laden terminal bulbs
Culture negative peripheral ulcer / contact lens related peripheral ulcer patho:
Gram+ bacteria colonisation of CL (S.aureus) > toxin release > antigen-antibody immune response > inflammatory cascade > neurophil/macrophage migration from limbal vessels > sterile inflammation w/epithelial defect / stromal infiltrate
Necrotising stromal HSK patho:
Live virus in stroma < immune-mediated response > neurtophil/macro. Influx > phagocytosis / proteolytic enzyme release > stromal loss
Dense infiltrates, oedema, necrosis/melting/thinning
Geographic / Metaherpetic ulcer patho:
G: immunocomp./steroids > extensive viral replication
M: poor epithelial healing of G > damaged epith. Migration
M has no live virus
Neurotrophic keratitis patho:
Viral migration/inflammation > Nerve damage > neural derived GF loss > devitalised epith. > spontaneous epith. Breakdown
Also caused by antiviral toxicity, immunocomp., HZO, LASIK, diabetic neuropathy
Not related to live virus
Immune Stromal HSK patho:
Antibody cascade against inactive viral antigens
Nummular infiltrates, oedema, diffuse/focal opacity
Leads to stromal thinning, scarring, opacification, ghost vessels
HSK keratouvitis patho:
Immune-mediated inflammation from viral particals remining in cornea > Ant. Uveitis w/wo active corneal disease
Flare/collection in trabecular mesh > trabeculitis / aqueous drainage loss > ^IOP
Iris inflammation > synechiae > patchy sectoral iris atrophy
Secondary glaucoma/cataracts
Herpes zoster epithelial keratitis:
epith. Damage via invasion/replication/cell lysis
Initial punctate epith. Keratitis (several lesions of live virus)
Forms pseudo-dendrites (5d)
Requires 800mg acyclovir 1w
Endothelial HSK patho:
Inactive viral antigens in endo. Post initial manifestation
Keratic precipitates, stromal oedema, ant. Chamber reaction/flare
Stromal white wessely ring > light haloes
Associated trabeculitis > ^IOP
Nummular stromal keratitis from HZO:
Antigen-antibody response > stromal neutrophil/macrophages
Several granular infiltrates, usually under epith. Ulcers
Requires FML qid w/ acyclovir 3%
HZO keratouveitis:
T-cell mediated response in uvea
Causes blur (spasm)
Ant. Chamber flare/cells, iris synechaie, corneal oedema, trabeculitis (or blockage from white BC), iris atrophy
Requires pred-forte 1% per 2h, w/homatropine 2% (reduce spasm pain)
Herpes zoster disciform stromal keratitis:
Late stage (1mo) from type 1 and 4 hypersensitivity > upregulated immune response
Inflammation of stroma (full depth), immune ring
Limbal vascular keratitis > ^IOP
Requires pred-forte 1% per 2h (opthal)
Post-herpetic neuralga
50% by 70y
Inflammation/damage of sensory nerves from viral reactivation > dysfunction of unmylenated nociceptors
Light hypersensitivity via mechanical nociceptor stimulation > severe pain (allodynia)
Sporadic pain w/o stimulation
Phases of epithelial wound healing:
Latent
Migration
Proliferation
Attachment
Barriers to corneal wound healing:
Nerve loss (DM/HSK) > substance-P/neurotrophic-GF loss
Basement membrane dysfunction (DM) > poor framework
Limbal loss (steven-johnson) > low epith. Production
Ocular surface inflammation (DED) > MMP-9 upregulation > epith. Damage
Lid abnormality > exposure > desiccation
Also hormone imbalance/CLs/malnutrition
Epithelial wound healing latent phase:
^metabolic activity
Damaged apoptosis
Gap junction loss, desmosome remodelling, hemidesmosome disconnection
Fibronectin matrix forms in lesion to aid migration
Epithelial wound healing migration phase:
Surrounding cells migrate via filapodia > monolayer
Multilayer migration follows w/ ^glycoprotein synthesis
Migration rate of 0.05mm/h
Epithelial wound healing proliferation phase:
Proliferation/differentiation > density/structure restoration
Limbal cells produce amplifying cells forming basal layer
Gap/tight junctions reformed
Epithelial wound healing attachment phase:
Hemidesmosome reattachment
If lesion passes stroma, complex reformation take 1-3mo w/risk of corneal erosions
Stromal wound healing:
Basement membrane disruption > cytokine influx (IL-1 / TGF-b) > IL-1 activation of kerocytes > differentiation to fibroblasts > migrate to lesion edge
Transforming GF-b activation of fibroblasts > diff. To myofibroblasts containing a-SMA > wound closure
Fibroblasts secrete new collagen/ECM > opacity > ECM organisation via specific apoptosis
Takes 3-4 years to remodel
Complications in stromal wound healing:
Myofibroblasts apoptosis / fibroblast inactivation > transparent scar
Myofibroblasts can remain > excess ECM > hypercellular scar > refractive changes (a-SMA stress)
Sjogrens syndrome:
Genetic/environment > autoantibody (anti-Ro/SSA, anti-La/SSB) production > Immune-mediated destruction of targeted exocrine glands > ADDE/Xerostomia (dry mouth)/peripheral neuropathy/joint pain
Associated with RA/Lupus (secondary)
Endothelial wound healing:
Initial loss of endo. Barrier / pump > water influx to stroma > opacity
Cell migration across lesion > polymegethism (^size) / pleomorphism (shape) > barrier restoration
Response after 6h, progresses at 1mm/day (usual 1w to heal)
General process of autoimmune reaction:
Genetic predisposition + environmental factors > antigen presentation of self-antigen + faliure of self tolerance > generation of autoantibodies and self-reactive T cells > inflammation and destruction of self tissues
Environmental triggers for autoimmunity:
Disruption to normal immune regulation > creation/activation of auto reaction
Infections, chemicals/toxins, hormone changes, physical/psych. Stress, compounded with genetic predisposition
Adaptive immune process in autoimmune:
Antigen presenting cells (dendritic/macro.) endocytose FB > process into peptide antigens > presented to naive CD4+ T cell via MHC on APC surface > Differentiate to T helper cell (Th1/2) > mediate inflammation via cytokines
T cells in autoimmune:
Th1: cell mediated with TFN and IFN-gamma
Th2: antibody mediated with interleukins
Autoantibodies in autoimmune:
Self reactive B cells > antibodies against self-antigens > Immune complex deposited in tissue > immune reaction
Common autoantibodies: rhematoid factor (RA), anti-nuclear antibodies in lupus
Activation of autoimmune response:
Molecular mimicry/self-presenting dendritic cell autoantigen exposure > autoimmune response > inflammatory cascades > cytokine release/macrophage recruitment > tissue damage
Sjogrens syndrome:
Genetic/environment > autoantibody (anti-Ro/SSA, anti-La/SSB) production > Immune-mediated destruction of targeted exocrine glands > ADDE/Xerostomia (dry mouth)/peripheral neuropathy/joint pain
Associated with RA/Lupus (secondary)
Giant cell arteritis patho:
Systemic vasculitis, usually >50yo women
Autoimmune against adventitial layer of large BV walls > thickening > narrowing of lumen > artery occlusion > infiltration of mononuclear cells in wall > giant cell formation
Myathenia gravis:
Auto-antibodies block AChR of striated muscle > immune mediated destruction > poor Ach uptake > fatigue
Multiple sclerosis patho:
Autoimmune against myelin > inflammation/demylination/secondary axonal damage > disrupted conduction
Affects ON, brain, spinal cord
Macula hole patho:
PVD > persistent vitreofoveal attachment > Ant/Pos traction
OR
Fluid motion in vit. > tangential traction on vitreo-retinal interface
Traction at fovea > pulls muller cell cone from foveal PRs > cystic lesion > dehiscence of cystic cavity > centrifugal displacement of photoreceptors
ERM types:
Idiopathic: most common, u/>50y, 10% bilateral, 90% w/PVD
Secondary: u/retinal detachment Sx, then disease, trauma, vit. Inflammation, BRB loss
T1DM patho:
Autoimmune against pancreatic beta cells > insulin loss > systemic hyperglycaemia > vascular damage
Graves’ disease patho:
Unknown trigger > production of IgG antibodies against thyroid stimulating hormone receptor
Activation of TSHRs > ^thyroid hormone production > hyperthyroidism
Thyroid ophthalmopathy occurs seccondary to Graves’
Lamellar macula hole patho:
An aborted macula hole
Inner retinal layers lost from foveal PVD but outer photoreceptor layers retained
Continued progression unlikely as vitreofoveolar separation has completed
Macula pseudo hole patho:
Similar to full-thickness holes
No loss of retinal tissue, with normal foveal thickness
Formed by perifoveal retinal distortion secondary to epiretinal membrane or vitreomacular traction
Muller cell cone:
Central glial component at fovea, maintains orient and placement of retinal foveal components.
CSR description:
Central Serous CHORIORETINOPATHY
Accumulation of fluid under retina and/or RPE, causing localised detachment of neurosensory retina and/or RPE
HT discription:
Hypertension is elevated BP
Stage 1: >140/90 mmHg
2: > 160/100
3: > 180/110
Malignant HT (1%): >200/140
BP = cardaic output*peripheral resistance
CSR patho:
*idiopathic
Abnormality in choroid/RPE > choroid BV dysfunction > fluid leakage/build-up under RPE > RPE function disruption > local external BRB loss > pooling under retina > neurosensory detachment from RPE
HT risks:
^heart rate (sympathetic fight/flight)
^blood volume (renal retention)
^BV resistance (arteriosclerosis)
Age, stress, smoking, obesity, physical inactivity
TED patho:
IgG against TSHRs cross-react with similar antigens in orbit soft tissue fibroblasts/adipocytes (TSHR mRNA)
Cross-reactivity > autoreactive T cells infiltration to orbit fat/muscle (initiation) > T-cells release cytokines stimulating fibroblast proliferation and GAG production > GAG water retention/cellular infiltration > orbit fat/adipocyte/EOM swelling
ERM patho:
Idiopathic: *PVD > ILM defects > triggering migration/proliferation of glial cells, and proliferation of hyalocytes remaining on ILM
Secondary: *Vit irritation(Sx) > proliferative vitreoretinopathy following liberation / proliferation of RPE and glial cells within vit cavity
Essential HT causes:
^BP > Arteriosclerosis/Arteriolosclerosis > lumen size loss / ^BV resistance
^BP > Atherosclerosis > atheromatous plaque in intima layer > thrombosis
Plaque formation in Atherosclerosis:
HT/DM/smoking/obesity > endo. Damage > ^vascular permeability > Leukocyte/lipid adhesion to endo > intima invasion > macro. Phagocytose lipoproteins > lipid-laden foam cells / inflammation > intima smooth muscle proliferation / ^ECM production > atheromatous plaque of leukocyte/lipid/ECM/smooth muscle
Late stage atherosclerosis:
Plaque enlarges > narrow lumen / ^BV resistance > ^BP
Plaque may rupture > leakage into blood > thrombosis > ^lumen occlusion
Plaque/thrombus may separate > emboli in smaller BV downstream
CWS:
Microvascular damage > NFL ischemia > NF swelling > adjacent NF compression > ^ischemia/swelling of axons
Swollen axons disrupt spacing > altered refractive composition > visible spot
Hypertensive retinopathy stages:
Vasoconstrictive
Sclerotic
Exudative
Related conditions > HT choroidopathy, HT optic neuropathy
HT sclerotic stage:
Chronic ^BP > media BV layer hyperplasia > intima thickening / hyaline degeneration >
^BV attenuation
^BV tortuosity (focal change in wall hardening)
^arteriolar light reflex from thickened wall (copper>silver wiring)
AV nipping (venous compression where AV share adventitial sheath)
HT vasoconstrictive stage:
HT > Vasocon. Factors (angiotensin II, adrenaline, vasopressin) released > retinal BV ^vascular tone > ^arteriolar narrowing (norm 1:3 > HT 2:3 AV ratio)
Vessels with arteriosclerosis show focal narrowing from loss of elasticity/immobility of hardened wall
HT exudative stage:
Late stage chronic HT > endo damage > BRB loss >
Microaneurysms (outpouching wall > tight junction strain > leak/haemorrhage)
Retinal/macula oedema/hard exudate
Retinal haemorrhages
Cotton wool spots
Retinal haemorrhages in HT:
Flame: NFL, bright red, arcuate, pools between axons
More common in HT than DM (BP in NFL arterioles)
Dot/blot: OPL/NFL, small, dark red, round
Damage to pre-venular capillaries, small from intraretinal compression
Pre-retinal / sub-hyaloid: ILM-NFL / ILM-Vit. Hyaloid. Appear as D- / Boat- respectivley
Associated with damaged superficial retinal arterioles
Hard exudates in HT:
Damaged endo./tight J. > plasma leak in retina > oedema
Fluid “dries” > retained lipid/debris yellow hard exudate > phagocytosed by macro.
Leakage usually self limiting > only hard exudate present on examination
Hypertensive choroidopathy patho:
Rare, following severe acute ^BP, usually young adult
Choroid BV without autoregulation
HT > ^vasoconstrictive factors > ^^choroid BV constriction > BV/capillary narrowing/occlusion > RPE necrosis (pale patches under retina) > sub-retinal exudates > localised serous RD
NAION from HT:
Non-arteritic anterior optic neuropathy
HT > blood flow loss in short posterior ciliary arteries > ON ischemia > ganglion cell axon swelling > oedema > loss of visual signal transmission > sudden painless VA loss / colour loss (red desaturation) / RAPD
Similar presentation to AAION (caused by autoimmune arteritis)
C/B retinal artery occlusion from HT patho:
Atherosclerosis > BV plaque > seperation > emboli (contains cholesterol/CA) travel upstream > occlusion in central/branch artery
Hypertensive optic neuropathy:
^BV constriction > decreased blood flow in short posterior ciliary arteries > ON ischemia > nerve fibre swelling / axoplasmic stasis
^intracranial pressure (from HT) > ON compression > axoplasmic stasis / swelling
Presents bilateral ON oedema
Late stage > ON atrophy: ganglion cell death > glial proliferation > pale OD
C/B retinal vein occlusion in HT:
Virchow’s triad > clot(thrombus) in vein > blood flow blockage > ^vein pressure > ^tortuosity/thickening > vein ischemia (deoxygenated blood stasis) > leakage > “blood and thunder” blot/flame haemorrhages, exudates, oedema
Causes sudden painless loss of vision
Virchow’s triad:
Endothelial injury
Stasis
Hypercoagulable stress
AV nipping > turbulent flow of venous blood > endo. Wall damage / stasis > hypercoagulability / thrombosis formation
RPE functions:
Transport from choroid/Retina
Tight junctions prevent passive diffusion from choroid
Melanin absorbs light (protect)
Phago. Outer seg. (PR debris)
Produces FGF, PDGF, VEGF, PEDF
AMD simple patho:
Oxidative/age related damage to PRs/RPE/Bruch’s/Choriocapiliaries
Loss of PRRPEBrMbCC complex symbiotic relationship results in macula degeneration
AMD patho for bruchs dysfunction:
Progression > soft drusen (>67um) > ^size/confluent > thickening/inflammation > calcification/degeneration of elastin/collagen layers of bruchs > hydrophobic barrier to fluid/nut. > loss between outer retina/choroid
AMD patho for RPE loss:
Nutrient loss / Drusen reabsorbtion > RPE ischemia / lipofuscin tox > ^dysfunction > apoptosis (seen as hypo/hyperpigmentation)
AMD patho for drusen formation:
Age/oxidation > dysfunctional metabolism of rod OS (^at macula) > ^metabolic by-products:
Basal laminar deposit (RPE/basement): collagen (cell stress)
Basal linear deposit (inner portion of bruchs): lipid/lippofuscin/complement (soft drusen; pro-inflammatory)
AMD patho for atrophic/non-exudative:
RPE loss > PR/CC dysfunction > largening chorioretinal geographic atrophy
RPE-produced trophic factor (VEGF) loss > CC atrophy > altered perfusion of choroidal vessels
AMD patho for neovascular/exudative:
Choroidal BV stenosis / Drusen inflammation > CC toxicity/death > CC perfusion loss > adjacent RPE hypoxia > angiogenic compound production (VEGF) > BV growth stimulation in CC > neovascular membrane (CNV) breaking bruchs > BRB loss > serum leak > PR loss
RP remodelling patho:
PR loss > RPE dysfunction >
RPE hyperplasia / inward migration (bony spicules)
Glial cell migration/proliferation (ON pallor)
PR loss > O2 consumption loss > BV attenuation
RPE degen. > BRB loss > intraretinal fluid leakage > macula edema
Exudative AMD description/causes:
10% cases
PR/RPE/BrMb/CC complex insulted by stenosis of choroidal BV, pro-inflammatory response from drusen (CC toxicity)
CC loss > loss of debris exocytosis > drusen formation
Serum leak via lack of tight junctions in ne BV
Non-exudative AMD description:
90% cases
Initial RPE hyperpigment, large confluent drusen
Followed drusen reabsorbtion > RPE death > hypopigment
End stage of geographic atrophy
RP patho:
Mutations > altered rhodopsin/RPE/PR-structure/PTD/Visual cycle > Rod PR/RPE dysfunction
Rod apoptosis > RPE dysfunction > retinal remodelling > altered signalling to cone PRs > apoptosis > central vision loss
Atypical RP types:
Diseases related-to/forms-of RP
Cone-rod dystrophy
RP sine pigmento
Retinitis puncata albescens
Sector RP
Pigmented paravenous chorioretinal atrophy
Syndromic RP types:
Syndromes associated with RP forms
Bassen-kornweig syndrome
Refsum disease
Kearns-Sayre syndrome
Bardet-Beidel Syndrome
Usher syndrome
Most common macular dystrophy:
Stargardt disease and fundus flavimaculatus (variations of same condition)
AD mutation in ABCA4 gene > rod OS metabolism dys. > ^RPE lipofuscin
VA 6/60
Round/pisciform yellow flecks on fundus
Forms of macula dystrophy:
Stargardt disease / fundus flavimaculatus
BEST vitelliform macula dystrophy
Sorsby fundus dystrophy
X-link juvenile retinoschisis
AD drusen
BEST vitelliform macular dystrophy patho:
Second most common macular dystrophy
Bestrophin gene (BEST1) AD mutation on chromosome 11q13
Altered RPE BEST ion channel > ^metabolic by-product above RPE
^by-product size > CNV / geographic atrophy
BEST disease first 3 stages:
Pre-vitreliform: abnormal EOG
Vitrelliform: vitrelliform lesion (yellow drusenoid PED) at macula 6/18
Pseudohypopyon: weight of material > inferior PED development
BESTs disease stages:
Pre-vitelliform stage
Vitelliform stage
Pseudohypopyon stage
Vitelliruptive stage
Atrophic stage
Sorsby fundus dystrophy patho:
Rare macula dystrophy
AD mutation in TIMP3 > altered inhibition of MMP-3 > by-product buildup in RPE
Characteristic yellow drusen-like deposits along arcades
BEST 4/5th stage:
Vitrelliruptive: lesion disruption (scrambled egg) 6/60
Atrophic: chorioretinal atrophy at macula > retina thinning > scarring ^6/60
X-link juvenile retinoschisis patho:
RS1 gene mutation > altered retinoschisin protein secretion from PRs > poor cell-cell adhesion > NFL splitting
Characteristic spoke wheel splits in macula
Autosomal dominant drusen:
EFEMP1 gene mutation > RPE matrix protein loss > drusionoid deposits
AMD by 20
Increasing drusen at macula > confluence > geographic atrophy/CNV by 50
Lebers congenital amurosis patho:
Severe AR rod-cone dystrophy in kids
Mutation in RPE65, CRB1, CEP290 > altered phototransduction cycle
Characteristic Franceshetti’s oculodigital sign of eye rubbing > keratoconus/deep set eyes
CSNB patho:
Congenital stationary night blindness is a group of inherited retinal dystrophies affecting PR/bipolar/phototransduction cascade
Loss of retinal signalling > vision loss / fundus changes / altered ERG
