lec 11: ocular surface agents part 1

what is the basic definition of dry eye disease according to the DEWS I study

Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface

what is the basic definition of dry eye disease according to the DEWS II study

Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.

what is the basic definition of dry eye disease according to the DEWS III study

Dry eye is a multifactorial, symptomatic disease characterized by a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface Inflammation and damage, and neurosensory abnormalities are etiological factors

what are the 3 layers of the tear film from anterior to posterior

lipid layer

aqueous layer

mucin layer

what is the role of the tear film

nutrients and O2 to the ocular surface epithelial cells

removes foreign materials

inhibits microorganism growth

fills in epithelial surface irregularities to maintain a smooth optical surface (vision)

what is the tear film a part of

our innate immune system

if you dont have a stable tear film, what will happen to ur vision

it’ll fluctuate 

what are the important role that eyelids play

tear film maintenance

secreting meibomian oil

spreading the mucin, aqueous, and lipids all over the ocular surface

if someone has SPK inferiorly what could be a cause of this

lagophthalmos OR lack of a complete blink

^ not spreading tears throughout the ocular surface

what stimulates the muscles to blink

optilight plus 

^ it improves the blink

what could be considered a fourth layer of the tear film

the microvilli on the corneal epithelium

they need to be intact for the tear film to adhere properly to the ocular surface

if the microvilli are damaged and continue to stay damage, what does that mean for our tear film

it could remain unstable 

what is the lipid layer

most anterior layer

between air and tear film

produced by meibomian glands

• with contribution from the glands of zeiss and moll

should be clear, liquidy, and colorless

what is the main purpose of the lipid layer

to reduce evaporation

what does bacterial lipase do to the triglycerides in the lipid layer

it transforms it into fatty acids and makes the meibum very thick 

what is the aqueous layer

middle layer

mostly water but it has a bunch of other components that are very important

contains IgA

has lactoferrin and lysozyme

main producer is the lacrimal gland

• accessory glands like krause and wolfring

part of our immune system and maintenance of the corneal epithelium

what can break down the cell wall of gram + bac

lysozyme

what is the mucin layer

the most posterior layer

sponge like meshwork that spreads the goblet cells across the corneal surface by the eyelids

produced by:

• conjunctival goblet cells

• crypts of henle

• glands of manz 

without a proper mucin layer what happens

tears arent being spread across the ocular surface like how theyre supposed to

areas that are deficient in mucin layer, what happens

they dont stick to the microvilli on the corneal epithelium → issue

mucin is needed to anchor onto the microvilli to provide a hydrophilic surface over the cornea and inhibit bacterial adhesion to the ocular surface

disruption or contamination (by lipids) to the mucus layer leads to what

local instability and trigger breakup of the tear film 

what is TBUT

tear fluorescein break up time

what is a normal TBUT

10 seconds

what is a normal schirmer’s score

<10 mm for 5 min

what does NIBUT mean

non-invasive break up time

what does 72% sensitivity mean for FBUT

FBUT was able to correctly diagnose 72% of the pts

but 18% of them were missed 

what does 62% specificity mean for FBUT

FBUT was able to correctly identify 62% of pts that do not have dry eye disease but that means that 38% were missed that acc do have DED

aqueous deficient

use schirmer’s

evaporative deficient

use TBUT

in the past dry eye was only two things:

aqueous deficiency and evaporative deficiency

NITBUT homestasis marker that means you have dry eye

< 10 sec

Osmolarity homestasis marker that means you have dry eye

> 308 mOsm/L in either eye or a difference of 8mOsm/L

ocular surface staining homestasis marker that means you have dry eye

> 5 cornea spots

> 9 conjunctiva spots

> 2mm lid margin length & > 25% width

^ use lissamine green for staining

if someone has symptoms and signs, do they have DED

yes

if someone has signs but no symptoms, what do they have

neurotrophic

they should feel it but they dont

FBUT homestasis marker that means you have dry eye

< 5 seconds

if someone has symptoms but no signs, what do they have

neuropathic pain

or transient discomfort like eye strain - uncorrected ref. error, or binocular issues 

what is ur break up time dependent on

blink rate and blink quality

what is the OSDI-6 cutoff for DED

> 4

what is the first step recommended for staging management and tx’ing DED according to DEWS II

educate the pt on the condition

modify the local environment

dietary modifications

identify and modify or eliminate systemic and topical meds

ocular lubricants of various types

lid hygiene and warm compresses

osmolarity has??

high selectivity but not great sensitivity 

if the osmolarity meter is very low do you have dry eye

no bc it is selective

if the osmolarity meter is very high does that always mean you have dry eye

no bc it is not very sensitive

what is the second step recommended for staging management and tx’ing DED according to DEWS II

non-preserved ocular lubricants to minimize preservative induced toxicity

tea tree oil tx for demodex

tear conservation

• punctal occlusion

• mositure chamber spectacles/goggles

• overnight tx’s

• meibomian gland expression

• lipiflow

in office tx for MGD

• intense pulsed light therapy

Rx drugs to manage DED

• topical antibiotic or abx/steroid combo applied to lid margins for anterior bleph

• topical corticosteroid

• topical secreatgogues

• topical non-glucocorticoid immunomodulatory drugs 

• topical LFA-1 antagonist drugs

oral macrolides or tetracyclines

what is the third step recommended for staging management and tx’ing DED according to DEWS II

oral secretagogues

autologous/allogeneic serum eye drops

• mimics our tears

• needs to be refrigerated

• dose: 6x a day

therapeutic contact lens options:

• soft bandage lenses

• rigid scleral lenses 

what is the fourth step recommended for staging management and tx’ing DED according to DEWS II

topical corticosteroid for longer duration

amniotic membrane grafts

surgical punctal occlusion

tarsorrhaphy (suture temporal eyelid)

salivary gland transportation

how should you target DED according to DEWS III

tear film deficiencies

eyelid abnormalities

ocular surface abnormalities

what is the glycocalyx layer

mucin + microvilli

etiologic driver tests for the lipid layer tear film deficiency

tear film lipid layer thickness/interferometry

meibomian gland expression 

meibum quality

etiologic driver tests for the aqueous layer tear film deficiency

tear meniscus height

meniscometry/schirmer/phenol red thread test

etiologic driver tests for the mucin/glycocalyx layer tear film deficiency

lissamine green/rose bengal staining

conj impression cytology 

etiologic driver tests for blinking/lid closure eyelid anomalies

incomplete blinking

etiologic driver tests for anterior bleph eyelid anomalies

eyelid biomicroscopy - greasy seborrheic or flaky staphylococcal 

eyelash base - cylindrical

dandruff - demodex

etiologic driver tests for MGD eyelid anomalies

pouting, missing, displaced gland orfiices

MG expressibility

meibography - truncated, dilated glands, “drop out”

telangiectasia

lid margin keratinization

tear film becomes unstable leads to what 

increased osmolarity

tear film evaporates

what does increased osmolarity lead to

cellular damage → apoptosis of the conj and cornea

what does apoptosis of the cornea & conj lead to

inflammation

what does inflammation lead to

cytokines release and MMP activates

what will cytokines being released and MMP’s being activated do

damage the goblet cells which impairs the mucin and leads to more tear film instability

what is cyclosporine historically

historically used as an immunosuppressant for organ transplant rejection prophylaxis, RA, and recalcitrant psoriasis 

^ anyone who had a kidney transplant would be on a cyclosporine to prevent rejection of the organ  

what is the mechanism of action of cylosporine

calcineurin inhibitor

reduced release of the cytokine interluekin-2 from the T cells

reduced T cell proliferation

max effects after 110 day T cell lifespan (they dont address the T cells that are about to form)

is cyclosporine A hydrophobic or hydrophilic

very hydrophobic molecule

with cyclosporine how are you preserving the conjunctival epithelial cells

cyclosporin A crosses the cellular membrane and gets into the mitochondria and inhibits the mitochondria from producing caspases which prevents apoptosis 

how does cyclosporine work on the T cells

it prevents inflammatory gene expression and prevents interleukin-2 from being expressed and it also promotes apoptosis of the T cell and eventually the T cell will be non-functional

what is restasis

topical cyclosporine A 0.05%

first immunosuppressant to be on the market for dry eye

comes in PF and a 30day BID PF dispenser

vehicle: refresh endura (castor oil)

how long does restasis take to work

3 months

LONGGG time bc it targets T cells that have already been activated

when do you get max effect of restasis

6 months

what is the dosage of restasis

BID (1 gtt every 12 hours)

does restasis work well as an anti-inflammatory to AKC, VKC, meibomitis, MG, GPC, and ocular rosacea

it is used off label for that but doesnt work well bc the cyclosporine conc is very dilute so it doesnt do anything to these conditions

what are the adverse rxns of restasis

BURNING, redness, tearing, discharge, foreign body sensation, itching, and blur

in what pts is restasis contraindicated

pts with active ocular infection (HSV or EKC) or a known hypersensitivity

what is cequa

topical cyclosporine 0.09% PF 

vehicle: NCELL tech

• uses nanomicelles composed of polymers that encapsulate cyclosporine molecules 

• delivers more of cyclosporine to cornea

how long does cequa take to work

1 month

when can you see significant improvement in conj staining with cequa 

2 months 

how do nanomicelles work in enhancing the ocular tissue penetration of cequa

the small size facilitates entry of cylcosporine into cornea and conj cells

nanomicelles penetrate the aqueous layer of the tear film

the nanomicelles then break up to release cyclosporine for penetration into ocular tissues

what is the structure of the nanomicelle

hydrophobic core and hydrophilic shell

what is the dosage for cequa 

BID (1 gtt every 12 hours)

what are the adverse rxns to cequa

pain on instillation of drops

conj hyperemia

what is cequa, restasis, vevye FDA approved for

increase tear production in pts with keratoconjunctivitis sicca

in what pts is cequa contraindicated

pts with active ocular infection (HSV or EKC) or a known hypersensitivity

what is vevye

topical cyclosporine 0.1%

non-preserved sol.

vehicle is perfluorobutylpentane 

• semifluorinated alkane that is colorless, amphiphilic, non-aqueous liquids that spread rapidly across the corneal surface  

it can deliver 22x more cyclosporine into the cornea than restasis

when do you see significant improvement in corneal staining with vevye

15 days

when do you see significant improvement in conj staining with vevye

29 days

what is the dosage of vevye

BID (1 gtt every 12 hours)

what are the adverse rxns of vevye

instillation site rxns (but less than restasis and cequa bc of the gentler vehicle)

decreased VA

in pts should you be cautious about using vevye

in pts with active ocular infections or known hypersensitivity

what is lifitegrast 

5% PF

an LFA-1 antagonist (not a calcinuerin inhibitor)

^ lymphocyte function associated antigen-1

it inhibits T cell activation by preventing binding of surface receptor to intercellular adhesion molecule commonly overexpressed on the dry eye surface

^ it not only works on T cells that have already been activated and it prevents future T cell activation 

so we know that restasis only works on the activated T cells, how does lifitegrast work

it prevents the activated T cells from binding to the ICAM-1 on the corneal surface resulting in damage and they prevent them from being activated

what is xiidra

the only FDA approved topical immunosuppresant inidcated to tx both the signs and symp of DED

what is the dosage of xiidra

BID (1gtt every 12 hours)

how long does xiidra take to work

2 weeks

how long does it take for xiidra to have max effect

6 weeks

what are the adverse rxns of xiidra

irritation

TASTES BAD (like the CAIs)

reduced VA

what pts is xiidra contraindicated in

pts with known hypersensitivity

what meds are the best anti-inflammatory meds

corticosteroids

what is eysuvis 0.25%

new loteprednol formulation

indication: dry eye flares not controlled by current therapy

80% of pts with dry eyes suffer flares

what is inveltys 1% 

new loteprednol formulation

indication: post-op inflammation and pain following ocular surgery

BID dosing