Pathophysiology of Ocular Surface Disease

Tear osmolarity single measure that gives information about the balance between what 4 things

- tear production

- evaporation

- drainage

- absorption

As volume of muco-aqueous (increases/decreases), concentration of solutes (increases/deceases) = (hyper/hypo)-osmolarity

muco-aqueous decreases

concentration of solutes increases

= HYPERosmolarity

What is the normal osmolarity value of blood serum

285-295 mOsm/l

What is the normal osmolarity value of tears

296-302 mOsm/l

Tear osmolarity is clinically measured from the:

lower lid tear meniscus

True tear osmolarity likely much (lower/higher) on surface of cornea as tear film much (thinner/thicker)

higher

thinner

(T/F) Local osmolarity spikes may occur in areas of tear breakup

TRUE

the liquid is evaporating in breakup but the minerals and components are still there so osmolarity value shoots up

Describe the core mechanism of Dry Eye cycle

- muco-aqueous tear components are reduced causing hyperosmolarity

- tear hyperosmolarity triggers cascade of immune response

- there is a release of inflammatory mediators and proteases

- this leads to loss of goblet cells, corneal epithelial cells and epithelial glycocalyx

- inflammatory mediators from activated T-cells increase damage to corneal surface

- damage induces tear film breakup which amplifies the hyperosmolarity potentiating the inflammatory cycle

List 4 contributing factors to Hyperosmolarity of tears

• tear film thinning during inter-blink interval

• decreased muco-aqueous production

• increased rate of muco-aqueous evaporation

(d/t poor lipid layer)

• decreased blink rate/incomplete blinking

________ is the first line of defense for the ocular surface, ______ is second

1st = eye lids

2nd = tear film

_______________ is the initiating stimulus for hyperosmolarity and ocular surface trauma

desiccating stress

________________ on the corneal epithelial cells is the ultimate trigger for inflammatory cycle

desiccating stress

What do corneal epithelial cells produce in response to hyperosmolar stress

- MMPs

- chemokines:

· TNF-𝛼

· IL-1

· IL-6

· IL-8

What role do MMPs play in healthy eyes

play role in turn-over of corneal epithelial cells and healing after injury

How do MMPs potentiate the iflammatory cascade

by cleaving pro-cytokines and altering chemokine gradients amplifying the immune response

Review the complicated flow chart from the DEWS II report on slide 9

core mechanism for DES = hyperosmolarity

trigger for hyperosmolarity = evaporation

ths induces a cycling of activating pro-inflammatory cytokines... causes damages then feed back to continue

inflammation damages the lacrimal & MGs... can't release their produced as needed so hyperosmolarity increases further and cycle repears

List 3 outcomes of ocular surface inflammation

- infiltration of lacrimal glands

(decrease aq.)

- potentiate pre-existing abnormal gland function

(decrease aq.)

- MG health & function

(increases meibum)

Inflammation causes a (decrease/increase) in aqueous production, what effect does this have

decrease

increases hyperosmolarity of the tears because less fluid to hold the same concentration of minerals

Inflammation causes a (decrease/increase) in meibum production

increase

the increase causes higher than normal meibocyte proliferation

because of the excretory mechanism, the faster proliferation interrupts the normal maturation process of the meibum as it moves from acini to orifice

normally proteins and keratin content is progressively decreased as it moves towards he orifice but when moving too fast they stay in the meibum which lead to altered fluidity and quality

How are Keratin Plugs formed

excess keratin from the meibum forms plugs at the orifices of the MG ehich then causes hyperkeratinization of the gland itself

What is the effect of desiccating stress on the acinar stem cells of the meibocytes, what are the 2 results of this

they become depleted

this leads to:

- early aging changes

- gland atrophy

What is the role of incomplete blinks in meibum stagnation

orbicularis and muscle of Riolan apply less squeezing force

causing weaker driving force for MG to secrete meibum

image slide 13

Meibum normally liquid at what temperature

28° to 32°C

(T/F) meibomian gland loss is required to be considered of having MGD

FALSE

do not need to have gland loss to have disease - atrophy is a downstream outcome

How does stagnant meibum ultimately lead to gland atrophy

if meibum is not continually flowing, it gets trapped & ductal occlusion leads to cystic dilation of the duct and ultimately gland atrophy

image slide 15

Inflammation is at the root of majority dry eye disease.... list the 4 downstream effects of inflammation

• Ocular surface damage

• Degenerative changes

• MG atrophy

• Neurosensory changes

List the 3 different neurosensory changes that can be seen as a downstream effect of ocular inflammation

• Increased nerve sensitivity

• Peripheral sensitization

(allodynia and hyperalgesia)

• Central sensitization

(neuropathic pain)

List 4 structural changes to the lid margin that are seen with chronic inflammation

• Thickening

• Irregularity

• Scalloping with MG atrophy

• Telangiectatic changes

(T/F) Telangiectasic vessels are present in healthy lid margins

FALSE

Telangiectasic vessels along the lid margin act as a pathway for what

pathway for pro-inflammatory mediators to reach ocular surface

List 5 iatrogenic factors impacting the tear film

• Drug-induced

• Ophthalmic surgery-induced

• Ophthalmic medication-induced

• Systemic disease-induced

• Hormonal influences

List 4 ways (mechanisms) in which drugs may induce dry eye

• decreased tear production (anticholinergics)

• altered nerve input and reflex secretion

• inflammatory effects on secretory glands

• direct irritation effects

How do anti-histamines induce DE

check table in notes

How do decongestants induce DE

check table in notes

How do oral beta blockers induce DE

check table in notes

How do diuretics induce DE

check table in notes

How do PPIs induce DE

check table in notes

How does Isotretioin induce DE

check table in notes

SSRIs increase the risk of DE by ____ fold

1.55

(T/F) Polypharmacy is a major problem in DES

TRUE

some pt can get away with one DE inducing drug but when there are multiple meds, will cause a problem

Sebum excretion reduced by ___% w/in 6wks of standard dosing treatment of Isotretinoin (accutane)

90%

(T/F) Accutane appear to affect the superior lid glands > inferior lid glands

FALSE

all glands in the lid seem equally affected

BAK is present in ≈___% ophthalmic meds

70%

List 3 ways that BAK induce DE

- disrupts lipid bilayers of cell membranes and cellular metabolic processes

- causes corneal epithelial cells to swell, lose intercellular tight junctions &desquamate

- continual exposure can decrease number of sub-epithelial nerves decreasing corneal sensitivity further decreasing tear production

How do topical PGAs induce DE

pro-inflammatory so promote increased inflammation in an already inflamed ocular surfac

How do topical beta blockers induce DE

main and accessory lacrimal glands contain β receptors - blocking them maydecrease tear production

Which class of glaucoma med is thought to potentially impair corneal wound healing through inhibiting sympatheticactivity of limbal stem cells

beta blockers

Lit 4 ophthalmic surgical procedures that are known to induce DE

- LASIK

- PRK

- Cataract extraction

- Blepharoplasty

How does LASIK induce DE

creation of corneal flap severs nerves in sub-basal plexus... recovery of sensitivity is variable

How does PRK induce DE

creation of corneal flap severs nerves....

however less risk for dryness as deeper corneal nerves not severed

How does Cataract extraction induce DE

• meds during/after procedure

• exposure desiccation during procedure•

• nerve transection (not as signif w/ small incision phaco)

• LRI

(limbal relaxing incisions)

How does Blepharoplasty induce DE

upsets the normal architecture of the lid

(best to send to oculo-plastic surgery)

List 9 systemic conditions that are known to induce DE

- Sjogren's Syndrome

- Chronic inflammatory disease

- RA

- IBD

- Myasthenia Gravis

- DM

- Thyroid dysfunction

- Parkinson's disease

- Psychological conditions

Sjogren's Syndrome pt have a higher risk of what 5 ocular complications

• Chronic conjunctivitis (papillary and follicular)

• Corneal melt/perforation/sterile ulcers

• Uveitis

• Episcleritis/scleritis

• Optic neuritis

Sjogren's Syndrome is mediated by autoantibody production and CD-4 T- and B-cells lymphocytic infiltration and destruction of _________

exocrine glands

____% of RA pt have persistent ocular dryness

11%

____% of RA pt have episodic ocular dryness

17.5%

Prevalence of ocular dryness in RA pt increases ≈___% for every decade of treatment

10%

List the 3 most common ocular manifestations of IBD

- episcleritis

- scleritis

- iritis

Upwards of ___% of IBD pt may experience dry eye

22%

Myasthenia Gravis causes ocular surface dryness secondary to what 2 things

- reduced blink completeness and frequency d/t orbicularis weakness

- lagophthalmos

>___% of Pts w/DM may have concurrent dry eye

50%

(T/F) Incidence of DE in DM pt increase with the presence of diabetic retinopathy

TRUE

List 3 mechanisms by which DM induces DE

- peripheral neuropathy... microvascular damage to corneal nerves disturbing LFU feedback loop

- insulin insufficiency...

normally mediates cellular function of the cornea & lacrimal glands, low insulin disrupts the biochemical balance

- inflammation... hyperglycemia triggers s/potentiates inflammatory cascad

How does Thyroid Dysfunction induce DE

- orbital tissue inflammation causing exposure

- lacrimal gland inflammation deceasing tear production

How does Parkinson's induce DE

decreased blink rate d/t decreased dopaminergic function

Up to ___% of Thyroid Dysfunction pt experience DE

85%

Which 3 sex hormones are thought to potentially alter the inflammatory process in the LFU to contribute to DE

- androgens

- estrogens

- progesterones

Androgens (decrease/increase) MG function & the quantity / quality of lipids

increase

(low/high) androgens activity may result in MGD

low

What is the relation between DE and prostate cancer

males using anti-androgen tx for prostate cancer show signs of significant MGD and ocular surface abnormalities

___________ appear to antagonize the actions of androgen with resulting suppression of lipid synthesis and development of MGD

estrogens

Estrogens are thought ot have a (direct/indirect) impact on MGs

indirect

How is function & structure of the Main Lacrimal Gland mediated by sex hormones

through regulation of gene transcription

There is evidence that Accessory Lacrimal Glands express genes for ______ and _______ receptors

androgen and progesterone

(T/F) The actions of hormones on the lacrimal gland appear to be sex-specific

TRUE

Decrease in MUC5AC expression in androgen insufficiency attributed to __________________, not ____________

attributed to :

compromised goblet cell function

not :

a decrease in the number of cells

Which sex hormone is involved in modulation of mucin production by conjunctival goblet cells

androgens

Thw conjunctiva is an _________-sensitive epithelium

estrogen-sensitive

(its cells display changes in level of cell maturation and possibly mucin production that parallel the variation in hormone levels over the menstrual cycle)

Conjunctiva of post-menopausal females more susceptible to what 3 things

- development of squamous metaplasia

- inflammation

- decreases in number of goblet cells

(T/F) Androgen deficiency alone appears to cause inflammation

FALSE

in absence of autoimmune disease, androgen deficiency alone doesn't appear to cause inflammation

Androgens can attenuate systemic autoimmune disease, and androgen deficiency is a factor in ____________-

Sjögren's Syndrome

The highest level of DE sx occur at day ____ of menstruation when estrogen levels are the (lowest/higher)

day 2

lowest

The lowest level of DE sx occur at day ____ of menstruation when estrogen levels are the (lowest/higher)

day 16

highest

Females on oral contraceptives report (lower/higher) levels of ocular symptom than normally menstruating females across all days of the cycle

higher

(OCPs suppression of estrogen may be causative factor)

(T/F) These has been found to be a mildly protective effect of alcohol consumption in older patients

TRUE

possibly due to alcohol-induced peripheral neuropathy leading to decreased corneal sensitivity and fewer symptoms

In females, chronic alcohol consumption may alter sex hormone levels increasing ______ and decreasing _________ with resulting increased conversion of _________ to _________

increasing estrogen

decreasing progesterone

conversion of androgens

to estrogens

Numerous studies show a decreased TBUT in smokers, what is the suggested mechanism behind this finding

- increased levels of circulating pro-inflammatory and decreased levels of anti-inflammatory cytokines

- free radicals and reactive oxygen species may trigger ocular surfaceinflammation

What is the suspectied mechanism of how caffeine induces DE

- speculation that diuretic properties may promote DE through systemic dehydration

(however, habitual intake does not have a significant dehydrating effect so seemingly unrelated to DE)