This document outlines several new treatments and technologies for dry eye disease. It discusses increased expenditures on dry eye medications from 2001-2006 driven by Restasis. Six new tools to treat dry eyes are described, including anterior segment OCT, osmolarity testing, LipiFlow, Inflammadry, Ziena eyewear, and intraductal meibomian gland probes. New artificial tear formulations and the use of diquafosol and cyclosporine for dry eyes are also covered.

1. New Trends in Ocular
Surface Treatment
J. Alberto Martinez, M.D.
27201-AS COPE Approved
December 9, 2012

2. OUTLINE
• Dry eye medication use and expenditures
• Six new weapons to attack dry eyes
• How to prescribe artificial tears
• Efficacy and safety of diquafosol ophthalmic solution in
patients with dry eye syndrome: a Japanese phase 2
clinical trial.
• Dry eyes and migraines: is there really a correlation?
• IntraductalMeibomian Gland Probes
• A randomized double-masked study of 0.05%
cyclosporine ophthalmic emulsion in the treatment of
meibomian gland dysfunction.

3. OUTLINE, CONT.
Squeezing the meibomian glands.
• Is topical ganciclovir effective for the treatment of
adenovirus conjunctivitis?
• NeurotrophicKeratopathy: New Treatment
Strategies
• Case presentation: Partial stem cell deficiency

4. Dry eye medication use and expenditures:datafrom
the Medical Expenditure Panel survey 2001 to 2006
• From the 2001 to 2006
• Medical Expenditure Panel Survey
• Data gathered from 147 unique participants aged
18 years old or older using the prescription
medicine, Restasis and Blephamide.
• The results:
▫ Dry eye medication use and expenditures increased
between the years 2001 and 2006, with the mean
expenditure per patient per year being:
 $55 in 2001 to 2002 (n = 29)
 $137 in 2003 to 2004 (n = 32)
 $299 in 2005 to 2006 (n = 86).

5. • This finding was strongly driven by the
introduction of topical cyclosporine emulsion
0.05% (Restasis; Allergan, Irvine, CA).
• In analysis pooled over all survey years,
demographic factors associated with dry eye
medication expenditures:
▫ Gender:
 Female: $244 vs. male: $122, P < 0.0001
▫ Ethnicity
 Non-Hispanic: $228 vs. Hispanic: $106, P < 0.0001
▫ Education
 Greater than high school: $250 vs. less than high school:
$100, P < 0.0001

6. Six new weapons to attack dry eyes
Tools used 5 years ago:
▫ Handing out samples of a lubricating eye drops
▫ Recommending increased hygiene around the eye
▫ Prescribing Restasis
▫ Inserting punctalplugs
• In 2012, eye care practitioners have multiple new
tools available to help patients at various stages of
the condition whose symptoms range from mild to
severe, making the management of dry eyes a much
more rewarding proposition, both clinically and
financially

7. New toys in dry eyes, anterior segment
• Anterior segment OCT
• Osmolarity measurements
• Lipiview/Lipiflow
• Inflammadry
• Zienna eyewear
• Intraductalmeibomian gland probes

8. Anterior segment OCT
• Measures accurately the tear meniscus. Anything
below 164 um is abnormal.
• Useful to quantify dry eye, compare efficacy of
treatments.

9. Anterior segment OCT
• ADVANTAGES:
• Rapid, non invasive, accurate
• DISADVANTAGES:
• Expensive, not that useful in day to day clinical
use (too many variables)

10. TearLabOsmolarity System
• Quickly and reliably during the patient’s visit
• “lab test on a microchip”
▫ requires a small sample (50 nL) of the patient’s tear
film, which is gathered by a special tip and then
inserted into the unit for measurement
• Accepted as a gold standard
• The test is cleared by the Food and Drug
Administration (FDA) and CLIA (Clinical
Laboratory Improvement Amendments)
• Enables doctors to perform the laboratory test in
their offices

11. Usefulness of Osmolarity
• Most (only?) objective, measurable test to
classify severity and to determine effectiveness
of treatment
• Normal: 300.8 +/_ 7.8
• Mild or moderate : 315.5 +/_ 10.4
• Severe: 336.7 +/_ 22.2
• Potential for doing better than asking patient:
Do your dry eye problem feels better or worse
with the treatment I am giving you?

12. • INTEREYE
DIFFERENCE Usefulness of
• Associated with disease
severity. Osmolarity
• Normal intereye
difference: 6.9 +/_ 5.9
• Mild/moderate: 11.7
+/_ 10.9
• Severe: 26.5 +/_ 22.7
• Still, Osmolarity is only
a mesure of dry eyes
and does not provide a
treatment of point
toward a solution

13. LipiView
• The LipiView Analyzer uses interferometry
(specularreflexion) to take a high-resolution image of
the lipid layer. It measures the lipid layer (normally
60 nanometers). Thin lipid layer is highly correlated
with MGD and patient symptoms

14. LipiFlow
• Rests on the sclera without touching the cornea
• Heat and pressure are directed at the meibum, effectively massaging
the structures to soften and release the obstruction that
characterizes meibomian gland dysfunction
• The treatment works by increasing blood flow around the
meibomian gland, thus facilitating heat transfer, and, secondly, by
mechanically removing blockage in the passages
• BUT: most payers, including Medicare, consider this procedure to
be “experimental and investigational” and therefore not covered
• The device costs about $100,000 and the disposable eye cups for
each patient use costs about $650 a pair.

16. Lipiflow
• Great possibilities. The “ultimate” warm compress
• Very expensive (both to eye doctors and patients) ,
not covered by insurance
• Unclear who are the best candidates (where is the
“sweet spot”) of this treatment?
• Only device in the area: Alan Glazier, OD, Rockville,
Md. aglazier@youreyesite.com
• Job opening…. 301-670-1212

17. Inflammadry
• Another “lab on a chip” type product
• Swab the fornices with an absorbent sponge
• Measures Metalloproteinase-9, a non-specific
marker of inflammation
• Like a pregnancy test: Negative or positive
• Non-specific to dry eyes but highly correlated
• Not yet approved in the US. Used in Canada

18. Dry eyes and nutrition
• We are in a unique position to address nutrition with our
patients.
• Many (most?) patients are unaware of the connection between diet and
ocular health
• We know that chronic inflammation plays a central role in dry eye
disase and MGD
• BEFORE you discuss fish oil, Talk about Vitamin C and E.
• Both of these vitamins have antioxidant properties. Reduce
inflammation
• Reccommed increased intake of vegetables and fruits (COLOR!) or a
supplement of 1000 mg of Vit C and 400IU of Vit E

19. Nutrition: Essential Fatty Acids
• Essential because body can not synthesize them, they have to be
obtained from diet
• Conpsumption of omega 3 fatty acids has DECREASED dramatically in
the last 100 years. Why: they are very susceptible to light and heat.
Easily becomes rancid: Not good for supermarket shelves
• While omega 6 has INCREASED. Why? More resistant to decay, better
shelf life.
• This “flipped” ratio has been found to be pro-inflammatory.
• Sources of Omega 3 and 6: Cold water fish (sardines, salmon,trout etc),
nuts and seeds, vegetables, nuts and seeds.
• We must avoid saturated, oxygenated fats and increase essential fatty
acids

20. Dry Eyeand Nutrition. Fish oil
multiple studies show a decrease in
inflammation
• Most ophthalmologist pooled, take fatty
acid supplements
• At VO we prefer “Hydroeyes” (Science-
based health) for it has several oils (GLA,
EPA and DHA) and vitamins (a, E,C and
B6) proven to improve dry eyes.
• A more “hardcore” (liquid oil) alternative:
Udo’s oil. (a 2:1:1 ratio of Omega 3:6:9)
• Also beneficial for skin, brain, joints,
immune system

21. ZienaEyewear
• Sunglasses frame that was specifically developed for
women with DED
• It contains an eyecup that magnetically attaches to
the frame and can be removed for cleaning. The
eyecup is well hidden behind the frame
• Discrete way of locking moisture, a proven relief for
dry eyes.
• May be helpful to reduce use of medicines in some

22. IntraductalMeibomian Gland Probes
• We all have seen obstructed meibomian Glands
• Obstruction is caused by increased viscosity
• Many orifices also exhibit keratinization.
• Inspisated glands lead to swelling, inflammation
and pain
• Decreased meibum production leads to
evaporative dry eyes
• Warm compresses often are not sufficient to
unplug the glands
• Need at least 5 working glands per lid

23. IntraductalMeibomian Gland Probing
• Indications:
• Swollen tender lids, symptomatic MGD
• Procedure:
• Slit lamp, topical anesthesia (lidocaine jelly)
• Disposable probes 1mm-6mm probes. Can
deliver steroids through probe
• Must continue MGD Rx: Doxy, Omega 3 etc

24. IntraductalMeibomian Gland Probing

26. OTC Drops: Telling the Tears Apart
▫ Is the optimum artificial tear for this patient preserved or not
preserved?
▫ Does the patient have more of an aqueous deficiency, mixed disease
or an evaporative form of dry eye?
▫ How severe is it?

27. How to prescribe artificial tears
• Self selection of medications is not a good idea
• Patients will get Walt-Mart or Safeway brand,
the most inferior tears in the market.
• Worse yet they may choose Visine

28. How to prescribe artificial tears
• USE TWO CRITERIA:
• 1. Underlying cause of dry eye? ( Aqueous
deficiency, mixed disease or evaporative form of
dry eye?)
• 2. How often the patient is instilling drops?
(severity of the disease). Ore than four
instillations per day: Go to preservative free

29. How to prescribe artificial
tears/Preservatives?
BENZALKONIUM CHLORIDE (BAK)
• It is essentially: Ammonia!.
• Deleterious effects to ocular surface are
innumerable: Destruction of epithelial cell walls,
destruction of intercellular tight junctions and
hemidesmosomes, destruction of corneal nerves,
destruction of bowman’s and even stroma.
• Also: axonopathy and degeneration of corneal
nerves (irreversible
neurotrophickeratopathy)

30. How to prescibe artificial tears
• Best preservative: NONE!
• Single-dose unit. Can twist-off, recap and use for
the entire day.
• A few good choices (all more expensive than
multiple dose preparations)
• Refresh (Allergan)
• TheraTears
• Soothe (Bausch + Lomb)
• Systane (Alcon)

31. How to prescribe artificial tears
• VANISHING PRESERVATIVE
• Preservativeturns into water or non-toxic
chemical when exposed to air or tear film
• Genteal (Novartis) has sodium perchlorate
• Allergan products: Purite (sodium chlorite)
Refresh optive

32. How to prescribe artificial tears
• LIPIDS
• An attempt to mimic biphasic nature of tears by
providing both aqueous and lipid components
• Guar in Systane
• Refresh Optive Advance and soothe provide a
lipid substitute

33. How to prescribe artificial tears
• VISCOSITY
• For people with more severe dry eyes
• “Watery” drops (i.e refresh plus) only last 3-4
minutes in the eye
• “sticky” viscous ones such as Celluvisc or
Systane ultra stay around the eye longer, but:
• Blurry vision, unsightly residue in lashes
• Good for patients with poor blink or
lagophthalmos or bell’s palsy. Best used at
bedtime

34. Osmolarity
• lower osmolarity tears may have a better effect on
the ocular surface.
• There are some tears that have ingredients that are
called osmoprotectants. They are taken up by cells,
and they blunt the response of the epithelial cells on
the surface of the eye to high osmolarity in the tears.
The Optive tears have osmoprotectants; some of
those are found in sports drinks also because people
can lose a lot of fluid and their blood may be a
higher osmolarity. There is pretty good scientific
evidence that they do help to protect cells.

35. How to prescribe artificial tears
• OSMOLARITY
• Increase osmolarity is a final common pathway
fro dry eyes
• Decreased osmolarity improves symptoms and
surface (TBUT, staining etc)
• Some tears (Optive)haveosmoprotectants that go
inside the cells and protect against increased
osmolarity

36. How to prescribe artificial tears
• Novasorb cationic emulsion.
Electrostatic attraction between
negatively charged droplets and
positively charged ocular surface
• Hypotonic to reduce osmolarity
• Lipid to lubricate and protect
• Available only through OD or MD
• Not a great deal of personal
experience yet

37. How to prescribe artificial tears
• OASIS TEARS
• Preservative free
• A viscoadaptive, non
linear molecule that
adheres to the surface
• Molecules are elastic,
remain in the surface
longer.
• Good personal
experience
• Sold at the doctor’s office
only

38. How to prescribe artificial tears
• RESTASIS (Cyclosporine 0.05%)
• Unknown mechanism. Inmunomodulator
• Decrease inflammation, increase tear production
• Compliance is difficult secondary to side effects (
burning, stinging, FB sensation)
• Expensive
• Undeniably, works well for some people
• Must suppress inflammation prior to starting
restasis

39. How to prescribe artificial tears
• RESTASIS.
• My regimen: Lotemax bid X 2 weeks, then start
restasis bid, taper off Lotemax over two weeks
• In severe dry eye patient with residual
symptoms but some improvement, may increase
Restasis up to qid (Positive dose-response
relationship)

40. How to prescribe artificial tears
• RESTASIS
• Has been shown to improve MGD
• Increases TBUT (in patients without aqueous
tear deficiency)
• Decreased lid inflammation
• Increased meibomian gland expressibility
• Unclear mechanism

41. Diquafosol in dry eyes
• Several studies have shown that Diquafosol is
effective in dry eye treatment
• Stimulates secretion of the three components of
tears: Mucin lipids and fluids
• Restores epithelial barrier function
• Approved in Japan in 2010
• In The US is in phase III clinical trials
• Brand name will be Prolacria
• Unclear when will be available

42. Dry eyes and migraines: is there
really a correlation?

43. Dry eyes and migraines?
• Yes!. There is a correlation
• Observational comparative study
• 66 patients, half with migraines
• The migraine sufferers have significantly worse
dry eye scores (TBUT, Schirmer, staining)
• Both migraines and dry eyes have inflammatory
basis.

44. Meibomian Gland Secretion secrets
A single MG is capable of secreting oil on demand
over the course of a working day ( approximately 9
hours)
Nasal MGs were the most likely to secrete upon
demand over the course of day compared with the
temporal and to a lesser degree the central MGs
Secretorycharacteristics of individual MGs examined
as a function of their location in the lower eyelid
does not change diurnally.

45. Squeez
ing the
MG’s

46. New Tool for Adenoviral Conjunctivitis
• In past studies, corneal and external disease
specialists' clinical diagnosis of adenoviral
conjunctivitis had laboratory confirmation in
only 20-25% of cases
• The RPS Adeno Detector Plus is a point-of-care
immunoassay that has 93% sensitivity and 96%
specificity.
• The monoclonal antibodies used in the assay
detect all 53 adenoviral serotypes.

47. New tool for Adenoviral diagnosis
• Rapid. 10 minutes
• Easy to use (just swab the conjunctiva)
• Single test use, no ancillary equipment
• CLIA waived. Can be performed by anybody in your
office
• Reimbursable: CPT 87809QW
• Cost/reimbursement?

48. Is topicalGanciclovir (Zirgan) effective for
the treatment of adenovirus
conjunctivitis?
A multicenter clinical trial is underway
Several studies have shown that Ganciclovir is
effective against adenovirus
Zirgan reduced the duration of the disease and the
incidence of subepithelial infiltrates
Inclusion criteria: Follicular conjunctivitis who test
positive on the RPS ( Rapid Pathogen Screening
Adeno Detector Plus Immunoassay)

49. Ganciclovir Treatment Goals
• Limiting the development of corneal infiltrates
(which can result in irregular astigmatism, glare,
photophobia and hyperopic shifts), the duration of
adenoviral shedding, and spread to the second eye
• Prevent the spread of disease by early and accurate
diagnosis and treatment
• To reduce the cost of lost days at work and school
• To afford specific antiviral treatment and avoid the
over-prescription of unnecessary, ineffective
antibiotics.
• To reduce the costs of treatment and diminish the
development of antibiotic associated allergies and
toxicities.

50. Adenovirus treatment
• SILVER BULLET: Betadine 5%
Pre-anethesize with tetracaine, NSAID. 4-5 drops
of betadine (if no Iodine allergies). Wait 60
seconds. Rub betadine with cotton tip swab
around lashes. Rinse with saline. Topical
steroids
A study is being conducted of a solution of 4%
betadine/0.1% dexamethasone

51. NeurotrophicKeratopathy:
New Treatment Strategies
• With loss of sensory function of the nasociliary branch of
the trigeminal nerve, neurotrophickeratopathy will
develop and result in degenerative corneal and
conjunctival changes of varying severity.
• Minor manifestations include:
▫ conjunctivaland corneal punctate epithelial irregularity
(fluorescein or rose bengal staining) with or without
decreased tear production or decreased tear film stability
(accelerated breakup time).
• However, such abnormalities can also progress to
involve persistent corneal epithelial defects, stromal
inflammatory reaction and most ominously, enzymatic
stromalysis with ulceration potentially leading to
perforation

52. Following herpes simplex keratitis, neurotrophic changes
result in persistent epithelial defect, stromal
inflammatory infilration and sterile stromalysis
(“melting”).

53. Conventional Management
• Traditional medical and surgical approaches include:
▫ preservative-free lubricants
▫ autologousserum drops
▫ topical steroid and non-toxic antibiotic prophylaxis, MGD
management
▫ therapeutic soft contact lenses
▫ punctal occlusion
▫ moist chamber glasses
▫ lid taping, lid malpositionrepair
▫ lateral tarsorrhaphy or Botoxinducedptosis
▫ cycanocarylatetissue adhesive
▫ conjunctival flap
▫ keratoplasty,
▫ Boston keratoprosthesis and herpes zoster vaccination.
• Conventional penetrating keratoplasty procedures have
variable success due to the poor healing capabilities of
neurotrophic tissues
• The risks of persistent epithelial defect and sterile ulcerative
stromalysis being of greatest concern.

54. New tools for managament of
neurotrophickeratopathy
• Autologous serum
• Prokera
• Now fully reimbursed
• Though very expensive

55. Selective debridment of
conjunctivalized epithelium to treat
stem cell deficiency

56. Stem cell deficiency
• 65 Y.O man with a history of alkaline burn.
• Presented initially 5 years ago with a melted,
perforated cornea.
• Underwent PK, achieved 20/30 was stable until
1 month ago. Presented with visual acuity of
20/200, partial stem cell failure
• Underwent selective epithelial debridment with
prokera, achieved 20/70 and improving.
• Avoided a stem cell transplant

62. Thank You