5/11/2015
OCULAR SURFACE DISEASE –
THE MEDICAL BUSINESS OF DRY EYE:
A COMPREHENSIVE COURSE ON OSD
EVALUATION, DIAGNOSIS AND
TREATMENT STRATEGIES
Jack Schaeffer OD FAAO
Bill Townsend OD FAAO
Melissa Barnet OD FAAO
Dr Jack L. Schaeffer
financial disclosure form
Alcon
Allergan
AMO / Abbott
Bausch and Lomb
Ciba Vision
Cooper Vision
Essilor
Hoya
Inspire
Optos
Optovue
Zeis Vision
The OSD Symposium
one and two

24 Doctors




22 Ods
2 MDS
30 Doctors
15 industry partners
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The OSD Wellness Initiative

OD’s
Need education
 Staff Training
 Change the culture
 Inform the Public


I Care
The OSD Wellness Initiative

Pre Screening

Diagnosis

Treatment

Patient Education
The OSD Wellness Initiative

Preventive Medicine
Dermatology
Dentistry
 Psychology ( behavior modification)

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DEWS

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.
Underlying Causes of Dry Eye Disease
Aqueous Deficiency
Pemphigoid
Neurological
Lupus
Stevens-Johnson
Mucin
Deficiency
Lipid Deficiency
Inflammation
Sjögren’s Syndrome
Ocular Surface Disease
Combination
Deficiencies
Dry eye is not just a
disease,
it’s a complex, multifactorial disorder.
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Environmental Factors

Visual Tasking




anti-histamines
alcohol
Arid Conditions


www.ratical.org
Foods/Drink


computer use
Systemic
Medications
Southwest
www.vrcbvi.org
www.wmin.ac.uk
Windy
Environments

uk.news.yahoo.com
air conditioning, forced
heat
Factors Influencing Dry Eye

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Age
Gender
Arthritis
Osteoporosis
Gout
Lens Surgery
Contact Lens Wear
Blink Disorders
Lid Disease
Nutritional Problems
Rheumatoid Arthritis
Thyroid Problems
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LASIK Surgery
Cosmetic Surgery
Mechanical Disturbances
Exposure Keratitis
Entropion
Ectropion
Symblepheron Formation
Large Lid Notches
Lagophthalmos
Incomplete Blinking
Dellen Formation
Illumination
Systemic Medications
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Time of Day
Temperature
Humidity
Air Movement
Allergies
Change in
Environment
Reading
Preservatives in
Topical Eye
Medications
Watching Movies
Sleep
Prause JU, Norn M. Relation Between Blink Frequency and Break-Up Time. Acta Ophthalmol. 1983; 61: 108-116.
Cho P, Cheung P, Leung K, Ma V, Lee V. Effect of Reading on Non-Invasive Tear Break-Up Time and Inter-Blink Interval. Clin. Exp. Optom. 1997; 80: 62-8.
Tsubota K, Seiichiro H, Okusawa Y, Egami F, Ohtsuki T, Nakamori K. Quantitative Videographic Analysis of Blinking in Normal Subjects and Patients with Dry Eye. Arch.
Ophthalmol. 1996; 114(6): 715-720.
Nally L, Ousler GW, Abelson MB. Ocular discomfort and tear film break-up time in dry eye patients: a correlation. IOVS 2000; 41(4): 1436.
Collins M, Seeto R, Campbell L, Ross M. Blinking and Corneal Sensitivity. Acta Ophthalmologica 1989; 67(5): 525-531.
Abelson MB, Holly FJ. A tentative mechanism for inferior punctate keratopathy. Am. J. Ophthalmol. 1977; 83: 866-869.
Doane MG. Dynamics of the Human Blink. Ber. Disch. Ophthalmol. Ges. 1980; 77: 13-17.
Kaneko K, Sakamoto K. Spontaneous Blinks as a Criterion of Visual Fatigue During Prolonged Work on Visual Display Terminals. Perceptual and Motor Skills 2001; 92(1):
234-250.
Dry Eye Etiology
Tear
Deficient
Evaporative
Oil Def. Lid Related Contact Lens
Sjogrens
Non-Sjogrens
Lacrimal Lacrimal
Deficiency Obstruction
Autoantibodies
Surface
Change
Reflex
NEI Workshop - Classification of Dry Eye (1995)
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Tear Film Instability


Note that a patient may have one or more
of these deficiencies—they are not
mutually exclusive
Aqueous Deficiency


Cause: insufficient tear production by
accessory and primary lacrimal glands
Sign: low Schirmer (tear volume/flow) score,
tear meniscus height (better measurement)
Tear Film Instability (cont)

Mucin Deficiency
Cause: insufficient or unhealthy mucin
production
 Sign: rapid tear film break-up time (TFBUT)


Lipid Deficiency
Cause: meibomian gland dysfunction (MGD)
causing insufficient or unhealthy lipid
production
 Sign: irregular meibomian gland expression,
fast TFBUT

DRUGS ASSOCIATED WITH
DECREASED TEAR PRODUCTION

-Adrenergic-blocking, Anti-anginals and Antihypertensives
(e.g. Atenolol, Practolol, Propranolol)

Tricyclic Anti-depressants

Oral Anti-histamines
(e.g. Amittriptyline, Doxepin)
(e.g. Loratadine, Clemastine, Hydroxyzine, Ceterizine,
Fexofenidine)

Alkylating Immunosuppressives

Diuretics
(e.g. Busulfan, Cyclophosphamide)
(
Ti
t
)
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Role Of Inflammation





Inflammation present in SS-KCS and nonSS KCS
Inflammation present in lacrimal glands,
conjunctiva and meibomian glands
Mediated by proinflammatory cytokines in
tears
Delayed tear clearance accentuates effect
Inflammation adversely affects neural
transmission
PHYSIOLOGY OF THE
DRY EYE

Pathologic
 Collagen
vascular diseases or
Autoimmune diseases
Rheumatoid Arthritis
Lupus Erythematosis
 Sjogren’s Syndrome
 0.4 % incidence
 95-98% women
 Fibromyalgia


PHYSIOLOGY OF THE
DRY EYE

Marginal
Contact lens wear--spk
Keratoconus
 Associated with GPC and/or blepharitis
 Meibomian gland dysfunction(mgd)
 EBMD (map-dot dystrophy)
 Acne Rosacea (involves mgd, blepharitis,
dry eye and leads to rosacea keratitis)


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PHYSIOLOGY OF THE
DRY EYE

MEDICATION INDUCED
 Antihistamines
 Diuretics
 Dermatologic--i.e.
Accutane
 SSRI’S (Selective Serotonin Reuptake
Inhibitors--i.e. Prozac, Paxil, Zoloft,
Lexapro, (Welbutrin- to a lesser degree)
 SSRI/NorEpi RI Combination—ie.
Cymbalta
PHYSIOLOGY OF THE
DRY EYE

HRT INDUCED




Women on estrogen therapy (HRT) had a 69%
greater risk of dry eye syndrome
Women on estrogen plus progesterone/progestin
had a 29% greater risk of dry eye syndrome
Risk of dry eye increased 15% for every three
year interval on HRT
38% of Postmenopausal women in the U.S. use
HRT--translates into millions of women
Brigham and Woman’s Hosp. study—Nov. 2001, JAMA
Dry Eye Evaluation

Vision care Exam
CONVERSION

Medical Exam
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Examination





Adnexa
Lids / Lid Margins
Tears
Conjunctiva
Cornea
EXAMINATION

ADNEXA
Dermatological Inflammation
Dermatochalasis
 Rosacea



LIDS/ LID MARGINS
Infectious
Inflammatory
 Allergic
 Physiologic( Lagophthalmos)


Lid Disease




Blepharitis
Lid Wiper Epitheliopathy LWE
Meibomian Gland Disease MGD
GPC

To be covered later in presentation
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DIAGNOSTIC TESTS

EXTERNAL EXAMINATION
 THE

CRANIAL NERVE FUNCTION
For a 7th nerve palsy w/incomplete blink on
one side
 Leads to asymmetric dry eye or exposure
keratitis
 THE
HANDS
For typical arthritic changes suggestive of
Rheumatoid or Osteoarthritis
 Heberden’s Nodes--Nodular Swelling of
Distal Joints

EXAMINATION

CONJUNCTIVA
Goblet Cell function (ekc/post-op)
Staining
 Mechanical abnormalities


EXAMINATION

CORNEA
Staining
Topographical
 Hypoxia
 Secondary Infectious/Inflammatory
 Dystrophy


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DIAGNOSTIC TESTS

TEAR EVALUATION
 Tear
Meniscus
 TFBUT
 Osmolarity
 Evidence of Fluorescein Staining
 Tear Consistency-i.e. thickness,
debris, evidence of meibomian
gland oil and sebaceous secretions
 Shirmers
Neural Feedback Loop
The Healthy Tear Film
Composed of mucin, proteins, aqueous and lipid components.
Mucins are critical for the viscosity of the tear film.
Lysozyme and lactoferrin have antimicrobial functions.
Immunoglobulins such as IgA, IgG, and IgM have protective
functions.
• Many growth factors, including epidermal growth factor (EGF),
are found in the tears.
•
•
•
•
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The Healthy Tear Film
• Lysozyme and lactoferrin are the most abundant proteins.
• Lysozymes
– Enzymes that kill bacteria and viruses
• Lactoferrin
– Proteins that prevent or slow bacterial growth
The Healthy Tear Film
• Healthy tears - electrolyte concentrations are maintained to
ensure correct osmolarity.
• Osmolarity is important for many aspects of epithelial and nerve
cell function.
The Healthy Tear Film
• A healthy tear film is important to the eye’s normal functioning.
– Optimizes visual refraction.
– Protects the ocular surface.
– Provides ocular surface comfort.
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Tear Film in Dry Eye
• With dry eyes, concentrations of growth factors and tear
proteins are reduced.
• There is also a decrease in mucin due to loss of goblet cells from
the conjunctival epithelium.
• This decreases the viscosity of the tear film.
Tear Film in Dry Eye
• Proteases are now activated.
• Activated proteases degrade the extracellular matrix and the
tight junctions between adjacent cells of the corneal epithelium.
• Activated proteases are also responsible for cleavage of
cytokines into an activated pro‐inflammatory form.
• There is an increase in electrolyte concentration which increases
tear osmolarity.
Cytokine IL-1
• Important mediator of inflammation and immunity.
• Involved in pathogenesis of many human
inflammatory diseases, including ocular surface
diseases.
• Important inducer of other inflammatory cytokines
such as IL‐6, IL‐8, TNF‐α, and GM‐CSF.
• Stimulates production of MMP enzymes.
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Cytokine IL-1
• While present in normal tears, it is increased in patients
with dry eye.
• IL‐1α tear concentration is strongly correlated with corneal
fluorescein staining in patients with dry eye.
• Believed to play a key role in the pathogenesis of dry eye.
MMP
• Tear MMP activity showed significant and positive correlation
with corneal fluorescein staining scores
(P < .001).
• Tear MMP activity showed significant and positive correlation
with abnormal superficial corneal epithelia in confocal images in
patients with confocal microscopy.
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Tear Meniscus Evaluation
Recurrent Erosion
ABMD
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DIAGNOSTIC TESTS
Schirmer--w/ or w/o anesthetic
 Phenol Red Thread Test

 Zone
Quick-represents fluid present in
the conjunctival sac
Fluorescein Staining
 Rose Bengal Staining
 Lissamine Green Staining
 Tear Osmolarity
 Collagen Plugs

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Schirmer Test
No consensus as to which method is best
Without anesthesia
measures reflex tear
secretion
With anesthesia
measures basal tear
secretion
Schirmer Testing



Test of both tear film volume and flow rate
that is neither relevant nor reproducible
Uses a 35 x 5-mm strip filter paper placed
within temporal third of lower lid
Normal results (measured at five minutes)






Unanesthetized: 15-mm or more
Anesthetized (basal tear secretion)
5 to 10mm
Eyes can be open or closed
Little variation in results with age
Necessary for documentation
Alternative: Zone Quick® - phenol red string
Schaeffer Shirmer
 Always
do this as the last test
 Place
strip in any part of the eye
 Count
to three
 remove
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Tear Osmolarity
TearLab
Ocular Surface
Disease
UPDATE 2011
Osmolarity Provides Improved Standard of Care
• Tear osmolarity is the most accurate diagnostic test for dry
eye disease
• Elevated osmolarity is the central mechanism causing
ocular surface damage
• Allows a physician to rapidly diagnose & classify patients with
a global assessment
– In combination with a slit lamp exam, physicians can
select therapies based on mechanism of disease and
severity
• Modulate therapy using a quantitative endpoint
Tomlinson A, IOVS 2006. DEWS Ocular Surf 2007
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New measurement options of the
Keratograph 5M
OCULUS TF-Scan - Tear meniscus height measurement
The NIKTMH measurement can be performed
under infrared light conditions now → no
influences on the tear film conditions!!
11.05.2015
•
Overview of the
curvature along the lid
•
Digital measuring of
the height and
automatic
documentation
•
Automatic calibrated
and digital measuring
of the TMH
B.Sc. Florian Winzig
55
New measurement options of the
Keratograph 5M
OCULUS TF-Scan NIKBUT (Non Invasive Keratograph Break-Up Time)
The NIKBUT measurement can be performed under infrared light
conditions now → no influences on the tear film conditions!!
11.05.2015
B.Sc. Florian Winzig
56
New measurement options of the
Keratograph 5M
OCULUS TF-Scan – Lipid Layer
The Lipid Layer:
The thickness of the lipid layer is
a key indicator of tear film stability
and evaporation!
Thin Lipid Layer
Thick Lipid Layer
11.05.2015
B.Sc. Florian Winzig
•
coat the underlying aqueous
thereby impeding evaporation
•
create a hydrophobic barrier to
avert the overflow of tears
•
act as a lubricant to prevent
friction between the eyelid and
ocular surface
•
facilitate in creating a smooth
refractive surface of good
optical quality
Thick Lipid Layer
57
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New measurement options of the
Keratograph 5M
OCULUS TF-Scan: Tearfilm Dynamic
The Tearfilm Dynamic:
Tear movement correlates
significantly with tear film
thickness!
• Slow movement is
associated with a thick lipid
layer and a high-viscous
tear film
• Rapid movement after a
blink is negatively
correlated with the tear film
thickness and the viscosity
B.Sc. Florian Winzig
11.05.2015
58
New measurement options of the
Keratograph 5M
OCULUS Meibo-Scan
11.05.2015
B.Sc. Florian Winzig
59
InflammaDry
RPS Technologies
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Dry Eye Disease Cycle of Inflammation1




Dry eye is often hidden until patients have progressed and experienced symptoms
Dry eye symptoms overlap with other ocular surface diseases, complicating diagnosis
Numerous clinical diagnostics exist, with no single method preferred
Most ECPs use one or multiple tests, symptom assessment and patient history to diagnose
[1] Definition and Classification of Dry Eye. Report of the Diagnosis and Classification Subcommittee of the Dry Eye Work Shop (DEWS). Ocular Surface 2007;5:75‐92. Dry Eye Disease and MMP‐9
Matrix metalloproteinases (MMP) are proteolytic
enzymes that are produced by stressed epithelial cells on the ocular surface1
 MMP‐9 in Tears
 Non‐specific inflammatory marker
 Normal range between 3‐41 ng/ml
 More sensitive diagnostic marker than clinical signs1
 Correlates with clinical exam findings1
 Ocular surface disease (dry eye) demonstrates elevated levels of MMP‐9 in tears1
[1] Chotiakavanich S, de Paiva CS, Li de Quan, et al. Invest Ophthalmol Vis Sci 2009; 50(7): 3203‐3209.
Dry Eye Disease and MMP‐9

Increased concentrations of MMP‐9 can be found in other diseases or conditions, including:
 Ocular rosacea
 Meibomian
gland disease
syndrome
 Corneal ulcers
 Corneal erosions
 Sjögren’s
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Importance of Detecting MMP‐9

Identifying elevated levels of MMP‐9 facilitates better management of…



Patients who present with signs or symptoms of dry eye
Patients having ocular surgery such as LASIK or cataract surgery
When elevated levels of MMP‐9 are not tested, confirmed, and treated prior to ocular surgery, the following complications may occur:




Less accurate pre‐surgical measurements lead to worse visual acuity outcomes1
Mild dry eye becomes severe dry eye
Asymptomatic dry eye becomes symptomatic, chronic dry eye2
Epithelial ingrowth or LASIK flap slippage3
[1] Trattler W, Goldberg D, Reilly C. Incidence of concomitant cataract and dry eye: prospective health assessment of cataract patients. Presented at: World Cornea
Congress; April 8,2010;Boston,MA. [2] Ambrosio R. J Refract Surg 2008; 24:396‐407. [3] Fournie PR, Gordon GM, Dawson DG, et al. Arch Ophthalmol 2010; 128:426‐436.
Normal Levels of MMP‐9
Literature meta‐
analysis supports that normal levels of MMP‐9 (ng/ml) in human controls range from 3‐41 ng/ml
[1] Acera A, Rocha G, Vecino E, et al. Inflammatory markers in the tears of patients with ocular surface disease. Ophthalmic Res. 2008 Oct; 40(6):315‐21. [2] Chotikavanich S, de Paiva CS, Li de Q, et al. Production and activity of matrix metalloproteinase‐9
on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci. 2009 Jul; 50(7):3203‐9. [3] Solomon A, Dursun D, Liu Z, et al. Pro‐ and anti‐inflammatory forms of interleukin‐1 in the tear fluid and conjunctiva of patients with dry‐
eye disease. Invest Ophthalmol Vis Sci. 2001;42(10):2283‐92. [4] Leonardi A, Brun P, Abatangelo G, et al. Tear levels and activity of matrix metalloproteinase (MMP)‐1 and MMP‐9 in vernal keratoconjunctivitis. Invest Ophthalmol Vis Sci. 2003;44(7):3052‐8.
[5] Lema I, Sobrino T, Durán JA, et al. Subclinical keratoconus and inflammatory molecules from tears. Br J Ophthalmol. 2009;93(6):820‐4. [6] Honda N, Miyai T, Nejima R, et al. Effect of latanoprost on the expression of matrix metalloproteinases and tissue
inhibitor of metalloproteinase 1 on the ocular surface. Arch Ophthalmol. 2010;128(4):466‐71. [7] Markoulli M, Papas E, Cole N, et al. The effect of contact lens wear on the diurnal profile of matrix metalloproteinase‐9 and its inhibitor in the tear film.
Poster presented at the 6th International Conference on the Tear Film and Ocular Surface: Basic Science and Clinical Relevance. Florence, Italy. 24 Sept 2010.
InflammaDry® Limit of Detection
Normal levels of MMP‐9 in human tears ranges from 3‐41 ng/ml
POSITIVE TEST RESULT
MMP‐9 ≥ 40 ng/ml
NEGATIVE TEST RESULT
MMP‐9 < 40 ng/ml
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MMP‐9 and Dry Eye Severity1
[1] Chotiakavanich S, de Paiva CS, Li de Quan, et al. Invest Ophthalmol Vis Sci 2009; 50(7): 3203‐3209.
MMP‐9 Levels in Two Types of Dry Eye
MMP‐9 Activity in Tear Samples
NL – Normal
MGD – Meibomian Gland Disease EVAPORATIVE DRY EYE
SS – Sjögren’s Syndrome AQUEOUS DEFICIENCY
P < 0.001 compared with normal subjects
[1] Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro‐ and anti‐inflammatory forms of interleukin‐1 in the tear fluid and conjunctiva of patients with dry‐eye disease. Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2283‐92.
Dry Eye Disease Testing Methods
1‐2
3
3
3
4‐5
3
[1] RPS InflammaDry positive agreement and negative agreement was compared to clinical truth in RPS clinical study: protocol #12‐0615. [2] Sambursky R, Davitt WF 3rd, Latkany R, et al. Sensitivity and specificity of a point‐of‐care matrix metalloproteinase 9 immunoassay for diagnosing inflammation related to dry eye. JAMA Ophthalmol. 2013 Jan;131(1):24‐8. [3] Versura P, Frigato M, Cellini M, et al. Diagnostic performance of tear function tests in Sjogren’s syndrome patients. Eye (Lond). 2007 Feb;21(2):229‐37. [4] FDA Section 510(k) number k083184 for TearLab™ Osmolarity System; May 5, 2009. [5] Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in the diagnosis and management of dry eye disease. Am J Ophthalmol. 2011 May;151(5):792‐798.
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Cyclosporine and MMP‐9


MMP‐9 expression was evaluated by immuno‐histochemistry. The mean percentage of MMP‐9 expression of the conjunctival
epithelial cells was significantly decreased. MMP‐9 expression was evaluated semi‐quantitatively by measuring cytoplasmic staining for MMP‐9.
[1] Gürdal C, Saraç O, Genç, et al. Ocular surface and dry eye in Graves' disease. Curr Eye Res.2011;36:8‐13.
Treatment of Dry Eye Disease


Elevated MMP‐9 may predict which patients will respond to anti‐inflammatory therapy.
Patients who test positive can be treated with one of the following:1‐3
 Cyclosporine
 Steroid
 Azithromycin
 Doxycycline
[1] De Paiva CS, Corrales RM, Villarreal AL, et al. Exp Eye Res 2006; 83(3): 526‐535. [2] Gurdal C, Genc I, Sarac O, et al. Current Eye Research 2010; 35(9): 771‐777. [3] Li DQ, Zhou N, Zhang L, et al. Invest Ophthalmol Vis Sci 2010; 51(11): 5623‐5629.
InflammaDry Product Overview





Detects elevated levels of MMP‐9 in tear fluid
Rapid: 10 minute results
Easy to use: can be performed by a nurse or technician
In‐office: point‐of‐care immunoassay test aids in diagnosis at the time of office visit
Low cost: no additional equipment required
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InflammaDry Intended Use
InflammaDry is a rapid, immunoassay test for the visual, qualitative in vitro detection of elevated levels of the MMP‐9 protein in human tears from patients suspected of having dry eye. InflammaDry is to be used to aid in the diagnosis of dry eye, in conjunction with other methods of clinical evaluation. This test is intended for prescription use at point‐of‐care sites.
InflammaDry 4‐Step Process
*
* Release the lid after every 2‐3 dabs. Allow the sampling fleece to rest along the conjunctiva for 5 seconds.
Ocular Surface Disease
Secondary to
Systemic Disease
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Patient /Busy Doctor







64 YOM
History of Dry eye with all signs and
symptoms
Restasis
UNG PM
PP
PFAT
Signs / symptoms vary at each visit over a
year
Systemic Disease
Diabetes
 Rheumatoid Arthritis

 Sjogren’s
syndrome
Thyroid Eye Disease
 Rosacea
 Sleep Apnea
 Graft Vs Host Disease
 Many others

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VITAL STAINS

Sodium Fluorescein



Rose Bengal






Premier dye of conjunctiva
Stains devitalized cells on
cornea and conjunctiva
Stains mucin strands
Stains unprotected tissue
Phototoxic, sting is dose
dependent, antiviral?
Lissamine Green



Epithelial defects
Accumulates intracell. space
Same purpose as RB
Less stinging
Fluramene
Fluorescein Staining
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Lissamine Green Staining
Exposure zone staining
with limbal sparing


Exposure zone staining
with limbal staining
Intense diffuse staining
of exposure zone,
limbal staining
Lissamine green detects dead or degenerated conjunctival cells
Degree of severity increases from left to right
Images from Dry Eye and Ocular Surface Disorders, 2004
Rose Bengal
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Tear Film Break Up Evaluation
0 seconds
1 second
2 seconds
3 seconds
4 seconds
5 seconds
6 seconds
16 seconds
Tear film break up is indicated by the
dark areas that appear on the cornea.
Caution: amount of fluorescein
instilled alters results
TBUT vs ABMD
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Causes of Clinical Dry Eye



Mucin deficiency

Goblet cell dysfunction

Epithelial surface disease
Aqueous deficiency

Lacrimal gland dysfunction

Keratoconjunctivitis sicca
Meibum deficiency

Meibomian gland disease

Evaporative dry eye
30
5/11/2015
Filamentary Keratitis
Filamentary Keratitis





62 yo female
VA 20/200
Pain OU 2 years
Third doctor in 2 years
AT prn
31
5/11/2015
Filaments adhere to the
cornea, causing discomfort
Epithelial cells
and mucin
bind to form
filaments
Blinking
stimulates
filamentary
traction and
corneal
microtrauma
Compromised
epithelial cells
become
desquamated
Inflammatory
stimuli induce
excess mucus
production
Corneal
inflammation
induces
epithelial
damage
32
5/11/2015
33
5/11/2015
Filamentary Keratitis

Debridement of filaments
Iris forceps
 5 office visits
 Weekly

Filamentary Keratitis
34
5/11/2015
Filamentary Keratitis
Medications : week 1

Lotemax

Qid

Refresh Ung

PF AT


Pm
Q I hour
Filamentary Keratitis

Month 2
Restasis tid
PF AT q 1 hour
 PF UNG pm


35
5/11/2015
Month 3
 Lacriserts am /pm
 Restasis
 ( consider Bandage Contact lens)
filaments to none
What is Missing
36
5/11/2015

Punctal Plugs

Mucomist

MGD treatment
Advanced Recalcitrant PEK


Autologous Serum
Amniotic Membrane
Sutureless Amniotic
Membrane

ProKera – Amniotic Membrane for wound
healing
Corneal Ulcer
Bullous Keratopathy
 Folds in Descemet’s
 Chemical Burns
 Mechanical Complications 2ary to graft
 Disruption of surgical wound
 Non-healing surgical wound


37
5/11/2015
The Amniotic Membrane
•
•
The amniotic membrane is the innermost lining of the
placenta (amnion)
Amniotic membrane shares the same cell origin as the
fetus
•
•
Stem cell behavior
Structural similarity to all human tissue
Inflammation is the Hallmark of
All Ocular Surface Diseases
Ocular Surface
Disease
Corneal
Inflammation
Conjunctival
Inflammation
Keratitis
Eyelid
Inflammation
Conjunctivitis
Blepharitis
Inflammation’s Effect
on Healing



Inflammation: the first sign of wound healing & is also the
hallmark symptom of all ocular surface diseases
Uncontrolled inflammation leads to:
 Chronic pain and discomfort/irritation
 Delayed healing, more tissue damage
 Vision-threatening complication, e.g., scar/haze
Effective control of inflammation is an important strategy to
promote healing and minimize the risk of scar/haze
Non-Resolved
Inflammation
Tissue Damage
Controlling Inflammation is Key to Preventing Tissue Damage!
38
5/11/2015
PROKERA®:
BIOLOGIC CORNEAL
BANDAGE



PROKERA® utilizes the proprietary
CryoTek™ cryopreservation process
that maintains the active
extracellular matrix of the amniotic
membrane which uniquely allows for
regenerative healing.
PROKERA® is the only FDA-cleared
therapeutic device that both reduces
inflammation and promotes scar less
healing
PROKERA® can be used for a wide
number of ocular surface diseases
with severity ranging from mild,
moderate, to severe
11
6
Insertion of Pro-Kera







Remove from inner pouch
Rinse with saline (prevents stinging from
preservation media
Apply topical anesthesia
Hold upper lid and have patient look down
Insert into superior fornix
Slide under lower eyelid
Check for centration
39
5/11/2015
Post-Treatment Protocol
Continue
medications
Apply Temporary
Tarsorrhaphy
(PRN)
- Tape
- Tegaderm
- “Breathe-Right”
nasal strips
CONFIDENTIAL AND PRIVILEGED Property of Bio-Tissue, Inc.
Do not reproduce or distribute.
40
5/11/2015
Possible Tape Tarsorrhaphy
PROKERA® Removal
 Topical Anesthetic
 Pull the lower eyelid
 Lift the lower edge of
PROKERA® using a Q-tip or
forceps
 Ask the patient to look down
 Slide the PROKERA® out
with gentle pressure on the
upper eyelid
CONFIDENTIAL AND PRIVILEGED
Property of Bio-Tissue, Inc. Do not
reproduce or distribute.
41
5/11/2015
42
5/11/2015
Recommended Treatment Severity Level 1
•
•
•
•
•
•
Patient counseling
Environment management
Preserved tears
Allergy eyedrops
Water intake
Hypoallergenic products
Recommended Treatment Severity Level 2
•
•
•
•
•
•
Unpreserved tears
Gels
Ointments
Topical cyclosporine A
Secretagogues
Nutritional support
43
5/11/2015
Topical Cyclosporine A
• Only prescription medication for dry eye.
• Increases tear production in patients with keratoconjunctivitis sicca
due to ocular inflammation.
• Contraindicated in patients with active ocular infections and a
hypersensitivity to any of the ingredients in the formulation.
44
5/11/2015
Topical Cyclosporine A
• Several mechanisms of action
• Prevents apotosis (programmed cell death in the epithelial
cells)
• Inhibits T cell activation and a variety of Th cytokines,
including IFN-g
Restasis
• Patients treated with Restasis® had a 191% increase in average
goblet cell density from baseline, compared to a 13% increase
using the vehicle after 6 months.
Restasis
• Improvement in Schirmer scores in 15% of patients using
Restasis® at 6 months versus 5% in patients using vehicle.
45
5/11/2015
Restasis Study
• Topical Cyclosporine A in the Treatment of Dry Eye:
A Systematic Review and Meta-analysis.
• Cornea 2014 May 8
• Zhou, XQ, Wei, RL
• Systematic review and meta-analysis of randomized
controlled trials on Cyclosporine A versus placebo in
treating DES to evaluate the treatment efficacy and
safety of Cycylosporine A
Restasis Study
• 12 randomized controlled trials
• 3034 eyes of 1660 participants
•
•
•
•
•
•
Statistically significant improvement
TBUT
Schirmer test with anesthesia
Ocular surface disease index
Schirmer test without anesthesia
Adverse events - 21%
Steroids
• Steroids decrease production of inflammatory cytokines and
prostaglandins by the epithelial cells.
• Less effect on T cell activation
• Caution of steroid side effects
– PSC cataracts
– Glaucoma
– Elevated intraocular pressures
– May reduce the eye's ability to fight off infection
or repair itself after injury
46
5/11/2015
Recommended Treatment Severity Level 3
• Tetracycyline
• Punctal plugs
Tetracycline
• Several mechanisms of action
• Anti-inflammatory
– Inhibits production and activity of inflammatory
cytokines
• Anti-microbial
• Inhibition of bacterial lipases
• Inhibition of keratinization
Tetracycline
• Contraindicated in
– Children less than 8 years of age
– Pregnant or lactating women
• May cause dental enamel abnormalities
47
5/11/2015
Punctal Plugs
• Inserted into the puncta in order to prevent drainage of liquid
from the eye.
• Punctal plugs are made of different materials.
Punctal Plugs
• Use temporary punctal occlusion with collagen plugs first.
• In order to determine that permanent plugs will not cause
excessive tearing.
• If improvement with temporary plugs, may insert permanent
silicone plugs.
Scleral lenses are large diameter
gas permeable lenses that rest
beyond the limits of the cornea
and extend onto the sclera.
48
5/11/2015
Punctal / Lacrimal Occlusion


Rationale for occlusion therapy:
 Diminishes tear drainage from the ocular surface
 Enhances contact time between tears & ocular surface
 Utilizes “normal tears”
 Natural complement of proteins, enzymes, buffers, etc.
Multiple modalities, manufacturers, products
 Collagen, silicone, acrylic polymers
 Intracanalicular vs. punctal occlusion
49
5/11/2015
50
5/11/2015
51
5/11/2015
Recommended Treatment Severity Level 4
•
•
•
•
•
•
Systemic anti-inflammatory therapy
Oral cyclosporine
Moisture goggles
Acetylcysteine
Punctal cautery
Surgery
Autologous Serum Eye Drops
(ASED)
• 20% autologous serum eye drops q2h while awake
• Receive approximately 50 to 55 bottles (3ml size with a 2ml fill)
of preservative-free ASEDs
• Store unopened bottles in home freezer for no longer than three
months.
• Opened bottles stored in the refrigerator
– Must be used within 48 hours or discard.
ASED
Tear components not found in artificial tear products
Epidermal growth factor (EGF)
Fibronectin
Vitamin A
All support the proliferation, maturation, migration and differentiation of corneal and conjunctival epithelia.  Serum contains IgG, lysozymes and complement, which have bacteriostatic properties. 




52
5/11/2015
ASED
 Renewed interested in ASED for severe dry eye by
 Rheumatologist Robert Fox, M.D., Ph.D., at Scripps
Memorial Hospital in California
 And ophthalmologist Kazuo Tsubota, M.D., of Keio
University School of Medicine in Tokyo
How to Obtain ASED
Donor health questionnaire and informed consent are signed.
Prep venipuncture site
40ml of blood is collected into six 8.5cc blood tubes
Collected blood is set aside to clot for two hours at room
temperature.
 Then the blood is centrifuged at 5,600 rpm for 10 minutes.




How to Obtain ASED
• Serum is filtered through a 25mm polyethersulfone disc
filter before mixing with saline.
• Filtration is performed to remove fibrin strands, which are
believed to lessen the effect of ASEDs.
• Each 8.5cc tube of blood yields approximately 4cc of serum
(24cc total).
53
5/11/2015
How to Obtain ASED
• 20% solution based on the concentration level of
transforming growth factor B1 (TGF-B1) in blood serum.
• TGF-B1 inhibits epithelial proliferation.
• In serum, the concentration of TGF-B1 has been found to be
five times that of tears.
• In order to obtain a 20% solution, 10cc of saline is removed
from a 50cc bag; then, 10cc of 100% serum is added and
mixed with the remaining 40cc of saline.
How to obtain ASED
 A single blood draw produces 100cc of 20% ASEDs.  100cc of ASED can yield 50 sterile 3ml dropper bottles, each containing 2ml of ASEDs.  1ml equals about 20 drops, each bottle yields approximately 40 eye drops. ASED Cost
• Cost for the blood draw and a three‐month supply of ASEDs is $300. • Average annual direct cost approximates $1,200 dollars. 54
5/11/2015
ASED Study
 The Application of Autologous Serum Eye Drops in Severe Dry Eye Patients; Subjective and Objective Parameters Before and After Treatment  Current Eye Research, Sept 2013  Prague, Czech Republic
 Jirsova K, Brejchova K, Krabcova I, et al.
ASED Study
• Evaluated the impact of ASED on the ocular surface of patients
with bilateral severe dry eye
• Compare the between clinical and laboratory examinations and
the degree of subjective symptoms before and after serum
treatment.
ASED Study
• Three-month treatment
• Improvement of ocular surface dryness and damage of the
epithelium.
• Improvement of dry eye after ASED treatment correlated well
with the clinical, laboratory and subjective findings.
• From the patients' subjective point of view, the positive effect of
ASED decreased with time.
• Still persisted up to three months after the end of therapy.
55
5/11/2015
SCLERAL LENSES
LACRISERT®
(hydroxypropyl cellulose ophthalmic insert)
A Novel Approach to Treating
Dry Eye Syndrome
Please see full Prescribing Information.
LACRISERT
(hydroxypropyl cellulose ophthalmic insert)
Indicated in patients with
moderate to severe dry eye
syndrome (DES), including
keratoconjunctivitis sicca.
Indicated especially in patients
who remain symptomatic after
an adequate trial of therapy with
artificial tear solutions.
Indicated for patients with
exposure keratitis, decreased
corneal sensitivity, and recurrent
corneal erosions.
Lacrisert [package insert]. Aton Pharma, Inc.: Lawrenceville, NJ; 2007.
56
5/11/2015
LACRISERT Insertion (cont’d)
Step 1
Step 4
Step 2
Step 5
Step 3
Step 6
Step 7
See www.lacrisert.com for an insertion guide and instructional video.
Instructions for using Lacrisert. Aton Pharma, Inc. Lawrenceville, NJ; 2007.
57
5/11/2015
Symptoms exacerbated by
• Diet low in Omega 3 or high in Omega 6
Fish Oil
• Fish oil supports the body’s natural
anti-inflammatory response.
• Women’s Health Study
• Cross sectional study of 32,470
women.
Relation between dietary n6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr 2005; 82:887–893.
Fish Oil
• Women who ate five servings of
fish per week had 68% reduced
risk of DES compared to those
who ate one serving.
Relation between dietary n6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr 2005; 82:887–893.
58
5/11/2015
Essential Fatty Acids
• EFAs (Omega-3 and Omega-6)
are not made by the human
body, but are required for
proper function of all cells
• Omega-3 fats – EPA and DHA
• Attain their highest
concentration anywhere in the
body within the ocular tissue
• Fish oil is the best source of
the omega-3 fats, EPA and
DHA
Stillwell W, et al. Chem Phys Lipids 2003.
Cordain L. AJCN 2005. Linus Pauling Institute, Corvallis OR 2006.
Sources of Omega-3 & Omega-6 Fats
Omega-3
 Fish: EPA and DHA; oily cold-water fish such
as sardines, anchovies, and salmon
 Plant: Alpha-linolenic acid (ALA); flaxseeds,
hemp, walnuts, and their oils; vegetable oils
Scientific evidence has determined that ALA is not
a
reliable source of EPA and DHA
Omega-6
 Plant: Linoleic acid (LA); vegetable oils
(soy, corn, sunflower, safflower)
 Animal: Arachidonic acid (AA); eggs,
dairy, and red meat
Effects of beef- and fish-based diets on the kinetics of n-3 fatty acid metabolism in human subjects. Am J Clin Nutr 2003;77;565–572.
Achieving optimal essential fatty acid status in vegetarians: current knowledge and practical implications. Am J Clin Nutr 2003;78:640S–646S.
Essential Fatty Acids – DHA, EPA,
and GLA
• Docosahexaenoic Acid (DHA)
–Visual development
–Structural lipid in retinal
photoreceptor and synaptic
membranes
–Protects from light, oxygen,
and age-associated damage
to the eyes
59
5/11/2015
Essential Fatty Acids – DHA, EPA,
and GLA
• Eicosapentaenoic Acid (EPA)
– Anti-inflammatory
– Reduces inflammation of
Lacrimal gland
Meibomian gland
Ocular surface
• Gamma-Linolenic Acid (GLA)
– Reduces circulating
inflammatory
cytokines associated with DES
– Precursor to PGE1, which
supports tissue moisture and
cellular health
Autoimmune Disease
• Rheumatoid Arthritis
o
o
o
o
2% of US population
More than 90% with RA have DES
50% have moderate to severe DES
31% RA have dry eye and Sjogren’s
Autoimmune Disease
• Sjogren’s Syndrome
o Aqueous tear deficiency and Dry mouth
o 9 /10 patients are women
o Primary – without connective tissue disease
o Secondary – confirmed connective tissue disease
60
5/11/2015
Sjögren's Syndrome
•
•
European-American consensus group
Two forms of Sjögren's syndrome
•
•
•
•
•
Primary Sjögren’s syndrome
Aqueous-deficient dry eye
Dry mouth with the presence of autoantibodies
Reduced salivary secretion
Positive focus score on minor salivary gland biopsy
•
•
•
•
Secondary Sjögren’s syndrome
All characteristics of Primary Sjögren's syndrome
With autoimmune connective tissues disease
Most commonly rheumatoid arthritis
Sjögren's Syndrome
•
•
Traditional testing
Autoantibodies as diagnostic markers
•
Anti-Ro / SSA
– 70% positive in Sjögren’s patients
Anti – La / SSB
– 40% positive in Sjögren’s patients
Anti-nuclear antibodies (ANA)
– 70% positive in Sjögren’s patients
Rheumatoid Factor (RH)
– Positive in many rheumatic diseases
– Performed for the diagnosis of rheumatoid arthritis (RA)
– Positive 60-70% of patients with Sjögren’s
•
•
•
61
5/11/2015
Sjögren's Syndrome
•
New studies additional autoantibodies in Sjögren's Syndrome to – Salivary gland protein 1 (SP‐1)
– Carbonic anhydrase 6 (CA6) – Parotid secretory protein (PSP)  Autoantibodies present in two animal models for Sjögren's Syndrome •
•
•
•
Occurred earlier in the course of the disease Patients with Sjögren's Syndrome also produced antibodies to SP‐1, CA6 and PSP
Antibodies found in 45% of patients meeting the criteria for Sjögren's Syndrome who lacked antibodies to Ro or La. SP‐1, CA6 and PSP – Useful markers to identify patients with Sjögren's Syndrome at early stages of the disease – Useful markers to identify those that lack antibodies to either Ro or La
The Sjö™ In‐Office Testing Kit
Sjö testing
•
•
•
•
Finger prick
Obtain a blood sample
Apply sample to the collection card
Send card to be analyzed
62
5/11/2015
Oral testing for Sjögren’s
• Salivary Flow
– Measures amount of saliva produced over a certain period of time
• Salivary Scintigraphy
– Nuclear medicine test that measures salivary gland function
• Salivary gland biopsy – Typically performed in the lower lip – Confirms inflammatory cell (lymphocytic) infiltration of the minor salivary glands
Sjögren's Syndrome
• Ocular surface disease due to disease of the lacrimal
functional unit
• Numerous mechanisms for lacrimal gland dysfunction
• Cholinergic blockade from autoantibodies to muscarinic
acetylcholine receptor 3
• Inhibition of acinar secretion by inflammatory cytokines
such as IL-1
• Cytokine-mediated epithelial cell death
• Replacement of acini by lymphocytes
63
5/11/2015
Sjögren’s
• New research • Clinically significant ocular surface disease • May be present with normal tear production and tear volume.
• Inflammatory mediators that cause ocular surface epithelial disease • Matrix metalloproteinases (MMPs) – Increased production of MMP‐3 and MMP‐9 • Inflammatory cytokines and T helper (Th) cell associated cytokines.
Autoimmune Disease
• Systemic Lupus Erythematous (SLE)
o Chronic autoimmune multisystem disease
o Dry eye most common feature
o Also have recurrent corneal erosions (RCE) and punctate
epithelial
loss
Autoimmune Disease
• Irritable bowel syndrome and Crohn’s
disease
o High incidence DES
64
5/11/2015
Jennifer, 22 year old Caucasian Female
•
•
•
•
Chief complaint of eyes feeling “tight”
Reports dry eyes
Discharge in the morning
Using two types of artificial tears without relief
• Medical history significant for Sjögren’s disease
• Uncorrected VA
• OD 20/20
• OS 20/20
Jennifer Examination
• 2+ meibomian gland dysfunction OU
• 2+ conjunctival staining OU
• Reduced tear meniscus OU
• 1+ inferior PEK OU, 2+ lisammine stain OU
• Tear break up time OD 2 seconds OS 2 seconds
• Normal intraocular pressures
• Normal dilated examination OU
Jennifer Treatment
• Eyelid hygiene including eyelid scrubs and warm compresses
• Cyclosporine 0.05% bid OU
• Non-preserved artificial tears as needed
• Lubricant ointment at night
• Frequent breaks on the computer
• Omega 3 fatty acids
65
5/11/2015
Jennifer
• Returned with much improved symptoms
• Eyes no longer red, no FB sensation, no burning, no itching
• Four years later, eyes are stable and patient is compliant with
treatment instructions
Thyroid Eye Disease
• Thyroid eye disease
o Common
o Due to thyroid hormone imbalance and exophthalmos-related
corneal exposure
Thyroid Disease
• DES a complication of an autoimmune condition related to
Hashimoto's thyroiditis and /or Graves' ophthalmopathy
• Graves' ophthalmopathy
– DES due to enhanced environmental exposure and
lid mechanical impairment
• Inappropriate lid closure caused by
– Superior eyelid retraction, eye globe proptosis, and
impaired blinking.
• All factors contribute to inadequate tear film lubrication on the ocular
surface and higher evaporation.
66
5/11/2015
Thyroid Disease
•
•
•
•
•
Thyroid gland – butterfly‐shaped endocrine gland Located in the lower front of the neck
Thyroid produces thyroid hormones
Secreted into blood and carried to every tissue in the body
Thyroid hormone helps the body – Use energy
– Stay warm – Keep brain, heart, muscles, and other organs functioning.
Thyroid Disease
• Lacrimal glands • Larger than controls in patients with DES and thyroid disease • Biopsies of salivary glands
• Infiltrating lymphocytes (mainly CD3+T) with a CD4+T / CD8+T
(ration 2:1)
• Activation markers
• Human leukocyte antigen (HLA) class II molecules • Interleukin (IL)‐2 receptor (CD25) Thyroid Disease
• Recent studies
• Coexistence between thyroid diseases and Sjögren's
syndrome
• Ocular surface inflammatory responses in both conditions
• Likely that dry eye in thyroid disease is an autoimmuneinduced response.
67
5/11/2015
Thyroid Disease
• Autoantibodies against thyroid stimulating hormone (TSH) receptor in patients with thyroid‐associated ophthalmopathy
(Hashimoto’s thyroiditis and Grave’s disease)
• TSH receptors present in the lacrimal gland • Autoantibodies present in Sjögren’s syndrome • Suggest mechanism where autoimmunity disrupts interaction of hormone and tissue due to antibody binding to hormones and / or receptors, leading to lacrimal gland dysfunction Thyroid Testing
•
Clinical exam - Thyroid palpation
•
•
•
Thyroid Enlargement:
Diffuse Enlargement
– Isthmus and lateral lobes, no
nodules. Grave’s disease,
Hashimoto’s thyroiditis, endemic
goiter
Single node
– Cyst, benign tumor, false positive
(only one nodule of multinodular
goiter detected).
– Elevates index of suspicion for
malignancy.
– Assess for risk factors: radiation
exposure, hardness, rapid growth,
fixation to surrounding tissue,
cervical LAD, male, others.
•
•
•
•
•
Multinodular Goiter
– Iodine deficiency
Soft
– Graves Disease , may have bruit
Firm
– Hashimoto’s thyroiditis,
malignancy, benign and
malignant nodules
Tender
– Thyroiditis
Systolic or continuous bruit
– May be heard over lateral lobes in
hyperthyroidism
Thyroid Testing
• Thyroxine (T4 – contains four iodine atoms)
• Major thyroid hormone secreted by thyroid gland • Amount of T4 produced by thyroid gland controlled by TSH
• Thyroid stimulating hormone (TSH)
• High TSH indicates thyroid gland failing due to problem directly affecting the thyroid (primary hypothyroidism)
• Low TSH indicates that person with an overactive thyroid is producing too much thyroid hormone (hyperthyroidism) 68
5/11/2015
Thyroid Treatment •
•
•
•
•
•
Thyroid hormone replacement
Iodine suppression
Immunomodulators
Local radiotherapy
Orbital decompression
Oral corticosteroids
Thyroid Treatment • Difficult to determine in literature if treatments contribute to dry eye development and / or progression • No clinical trials •
•
•
•
Study 9 years follow up Patients received treatment for Graves’ ophthalmopathy
25% DED New Treatment Option
• Methotrexate for the treatment of thyroid eye disease (TED)
• 36 consecutive patients with active TED
• Previously treated with corticosteroids but stopped due to side effects
• Two different weekly doses depending patient weight (7.5 mg or 10 mg)
• Evaluated retrospectively at 3, 6, and 12 months, compared with baseline data. • Clinical activity score (7‐CAS) – Statistically significant improvement *
• Visual acuity (VA) – no significant change • Ocular motility – improvement *
• Exophthalmos – no significant change
• Eyelid position ‐ no significant change
• May be considered an alternative treatment with TED who cannot tolerate steroids.
69
5/11/2015
Diabetes
• Diabetes
o 54% patients diagnosed with DES
o Chronic tear secretion deficiency, peripheral neuropathy, and
hyperglycemia leads to corneal epitheliopathy-producing
complications
o Tear proteins of diabetics are different from healthy subjects
o Reflex tearing decreased in insulin-dependent diabetics
Recommended Treatment Severity Level 1
•
•
•
•
•
•
Patient counseling
Environment management
Preserved tears
Allergy eyedrops
Water intake
Hypoallergenic products
Recommended Treatment Severity Level 2
•
•
•
•
•
•
Unpreserved tears
Gels
Ointments
Topical cyclosporine A
Secretagogues
Nutritional support
70
5/11/2015
Topical Cyclosporine A
• Only prescription medication for dry eye.
• Increases tear production in patients with keratoconjunctivitis sicca
due to ocular inflammation.
• Contraindicated in patients with active ocular infections and a
hypersensitivity to any of the ingredients in the formulation.
71
5/11/2015
Topical Cyclosporine A
• Several mechanisms of action
• Prevents apotosis (programmed cell death in the epithelial
cells)
• Inhibits T cell activation and a variety of Th cytokines,
including IFN-g
Restasis
• Patients treated with Restasis® had a 191% increase in average
goblet cell density from baseline, compared to a 13% increase
using the vehicle after 6 months.
Restasis
• Improvement in Schirmer scores in 15% of patients using
Restasis® at 6 months versus 5% in patients using vehicle.
72
5/11/2015
Restasis Study
• Topical Cyclosporine A in the Treatment of Dry Eye:
A Systematic Review and Meta-analysis.
• Cornea 2014 May 8
• Zhou, XQ, Wei, RL
• Systematic review and meta-analysis of randomized
controlled trials on Cyclosporine A versus placebo in
treating DES to evaluate the treatment efficacy and
safety of Cycylosporine A
Restasis Study
• 12 randomized controlled trials
• 3034 eyes of 1660 participants
•
•
•
•
•
•
Statistically significant improvement
TBUT
Schirmer test with anesthesia
Ocular surface disease index
Schirmer test without anesthesia
Adverse events - 21%
Steroids
• Steroids decrease production of inflammatory cytokines and
prostaglandins by the epithelial cells.
• Less effect on T cell activation
• Caution of steroid side effects
– PSC cataracts
– Glaucoma
– Elevated intraocular pressures
– May reduce the eye's ability to fight off infection
or repair itself after injury
73
5/11/2015
Recommended Treatment Severity Level 3
• Tetracycyline
• Punctal plugs
Tetracycline
• Several mechanisms of action
• Anti-inflammatory
– Inhibits production and activity of inflammatory
cytokines
• Anti-microbial
• Inhibition of bacterial lipases
• Inhibition of keratinization
Tetracycline
• Contraindicated in
– Children less than 8 years of age
– Pregnant or lactating women
• May cause dental enamel abnormalities
74
5/11/2015
Punctal Plugs
• Inserted into the puncta in order to prevent drainage of liquid
from the eye.
• Punctal plugs are made of different materials.
Punctal Plugs
• Use temporary punctal occlusion with collagen plugs first.
• In order to determine that permanent plugs will not cause
excessive tearing.
• If improvement with temporary plugs, may insert permanent
silicone plugs.
Recommended Treatment Severity Level 4
•
•
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Systemic anti-inflammatory therapy
Oral cyclosporine
Moisture goggles
Acetylcysteine
Punctal cautery
Surgery
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Autologous Serum Eye Drops
(ASED)
• 20% autologous serum eye drops q2h while awake
• Receive approximately 50 to 55 bottles (3ml size with a 2ml fill)
of preservative-free ASEDs
• Store unopened bottles in home freezer for no longer than three
months.
• Opened bottles stored in the refrigerator
– Must be used within 48 hours or discard.
ASED
Tear components not found in artificial tear products
Epidermal growth factor (EGF)
Fibronectin
Vitamin A
All support the proliferation, maturation, migration and differentiation of corneal and conjunctival epithelia.  Serum contains IgG, lysozymes and complement, which have bacteriostatic properties. 
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ASED
 Renewed interested in ASED for severe dry eye by
 Rheumatologist Robert Fox, M.D., Ph.D., at Scripps
Memorial Hospital in California
 And ophthalmologist Kazuo Tsubota, M.D., of Keio
University School of Medicine in Tokyo
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How to Obtain ASED
Donor health questionnaire and informed consent are signed.
Prep venipuncture site
40ml of blood is collected into six 8.5cc blood tubes
Collected blood is set aside to clot for two hours at room
temperature.
 Then the blood is centrifuged at 5,600 rpm for 10 minutes.
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How to Obtain ASED
• Serum is filtered through a 25mm polyethersulfone disc
filter before mixing with saline.
• Filtration is performed to remove fibrin strands, which are
believed to lessen the effect of ASEDs.
• Each 8.5cc tube of blood yields approximately 4cc of serum
(24cc total).
How to Obtain ASED
• 20% solution based on the concentration level of
transforming growth factor B1 (TGF-B1) in blood serum.
• TGF-B1 inhibits epithelial proliferation.
• In serum, the concentration of TGF-B1 has been found to be
five times that of tears.
• In order to obtain a 20% solution, 10cc of saline is removed
from a 50cc bag; then, 10cc of 100% serum is added and
mixed with the remaining 40cc of saline.
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How to obtain ASED
 A single blood draw produces 100cc of 20% ASEDs.  100cc of ASED can yield 50 sterile 3ml dropper bottles, each containing 2ml of ASEDs.  1ml equals about 20 drops, each bottle yields approximately 40 eye drops. ASED Cost
• Cost for the blood draw and a three‐month supply of ASEDs is $300. • Average annual direct cost approximates $1,200 dollars. ASED Study
 The Application of Autologous Serum Eye Drops in Severe Dry Eye Patients; Subjective and Objective Parameters Before and After Treatment  Current Eye Research, Sept 2013  Prague, Czech Republic
 Jirsova K, Brejchova K, Krabcova I, et al.
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ASED Study
• Evaluated the impact of ASED on the ocular surface of patients
with bilateral severe dry eye
• Compare the between clinical and laboratory examinations and
the degree of subjective symptoms before and after serum
treatment.
ASED Study
• Three-month treatment
• Improvement of ocular surface dryness and damage of the
epithelium.
• Improvement of dry eye after ASED treatment correlated well
with the clinical, laboratory and subjective findings.
• From the patients' subjective point of view, the positive effect of
ASED decreased with time.
• Still persisted up to three months after the end of therapy.
Homeopathic Treatment
• Tear Stimulation Eyedrops
• Stimulate the production of all three tear film layers • Two separate formulas
• One for women
• And one for men 79
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Homeopathic Treatment
• Five powerful broad spectrum ingredients
• Relieve symptoms caused from
inflammation due to aqueous deficiency.
Homeopathic Treatment – Ingredients
• Alumina HPUS 10x: Indicated for dryness of the eyes and other
mucous membranes due to lack of aqueous secretion, "Sjogren's
Syndrome".
• Arsenicum album HPUS 12x: Indicated for severe dryness due to
inflammation and ulceration.
• Nux moschata HPUS 6x: Nux m. is the main remedy indicated for
severe aqueous deficiency such as with Sjogren's Syndrome.
• Zincum met HPUS 10x: Indicated for extreme dryness,
inflammation and burning.
• Euphrasia (Eyebright) HPUS 5x: Eyebright is often referred to as a
"tonic for the eyes" and is indicated for inflammation of the conjunctiva,
cornea and lids, including meibomian glands. Symptoms include
redness, dryness, lachrymation and burning of the lid margin.
Homeopathic Treatment
• Oral Pellets
Same ingredients as the eye drops.
Higher potency.
Oral form.
May be used in conjunction with the drops to increase
effectiveness by applying dual administration routes with
multiple potencies.
• One to three pellets two times per day.
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Scleral “Shells” for Ocular Surface Disease
• 1943: Klein, M. Contact lens in cases of
neuroparalytic keratitis. (Br J Ophthalmol)
– 2 cases
• 1962: Ridley, F. Therapeutic uses of scleral
contact lenses. (Int Ophthalmol Clin)
– Review of 3,000 cases
• 1967: Gould, HL. Treatment of neurotrophic
keratitis with scleral lenses. (EENT Monthly)
– 87 cases
©2012 MFMER | slide‐242
• 1992: Kok, J. H. Treatment of ocular surface
disorders and dry eyes with high gas-permeable
scleral lenses. (Cornea)
– 15 of 47 eyes
• 1997: Pullum, K.W. A study of 530 patients
referred for rigid gas permeable scleral contact
lens assessment. (Cornea)
– 8.2% of 530 patients
• 2000: Romero-Rangel, T.P. Gas-permeable
scleral contact lens therapy in ocular surface
disease. (Am J Ophthalmol)
– 49 patients (76 eyes)
©2012 MFMER | slide‐243
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Rationale
• Continual hydration of corneal epithelium
• NO contact with corneal tissue
• Protection of a large portion of the anterior surface of the eye
• Potential for improvement in vision
©2012 MFMER | slide‐244
General Considerations
• Symptomatic relief only
• Additive therapy
• Lens surface considerations
• Potential for medication toxicity
©2012 MFMER | slide‐245
Scleral Lens Insertion
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Scleral Lens Insertion
• Fill scleral lens fully with fluid
Handling ‐ Lens Insertion
• Goal “bubble free” insertion
• Patient bends over so that patient’s face is parallel to the horizontal plane
• May use target for patient to look at (such as Amsler
grid) when training Solutions ‐ Application
• Single dose unit of non‐preserved 0.9% sodium chloride inhalation solution
• Prescription medication • Patient to obtain from pharmacy
• Rinse off conditioning solution on lens with non‐
preserved saline prior to lens insertion 83
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0.9% NaCl prescription example
Solutions – Unisol 4
• Sterile, buffered isotonic saline solution
• Contains sodium chloride, boric acid and sodium borate • Does not contain any preservatives
Solutions – Unisol 4
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Same pH as eye’s natural tears
Sterile in unopened container Does not remain sterile indefinitely after opening
Should not be used as an eyedrop
Does not contain chlorhexidine, thimerosal
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Solutions ‐ Application
• Non‐preserved carmellose sodium (Celluvisc) or carboxymethylcellulose sodium (Optive or Theratears) • Celluvisc may be helpful if there are handling issues or if patient is elderly
Scleral Lens Insertion
• Use plunger or three finger approach to hold the lens
• Three finger method
• Three fingers are thumb, index, and middle fingers (may use ring finger also)
• Hold eyelids open
• Place the lens on the eye Handling ‐ Lens Insertion
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Plunger method Hold eyelids open
Place the lens on the eye Release plunger if plunger is used
Prefer large plunger for insertion
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Train and retrain
application and
removal
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