Download The New Normal in Managing Dry Eye Disease

Volume 1, Issue 2
2013
A Learning Resource for Optometrists from the School of Optometry & Vision Science, University of Waterloo, and the School of Optometry, University of Montreal
The New Normal in Managing Dry Eye Disease
B Y S ARAH M AC I VER , OD, FAAO, M ICHELLE S TEENBAKKERS -W OOLLEY, OD, FAAO,
AND C. L ISA P ROKOPICH , OD, MS C
Although the symptoms associated with the group of ocular conditions known as “dry eye disease”
– or dry eye syndrome (DES) – are common, they continue to be the most challenging to manage.
Perceptions surrounding DES include the beliefs that few therapeutic tools significantly impact the
disease and that overall DES management, as a chronic disease, is inadequate. Identifying and treating DES patients will not only reduce the number of patients suffering a decreased quality of life
due to its debilitating symptoms, it will also enable optometrists to optimize their therapeutic management skills. This issue of Optometry Rounds reviews the recent changes in classification, evaluation, and diagnosis of DES. It also outlines the new tools in the management of DES that enable
optometrists to treat this chronic disease more effectively.
Marlee M. Spafford, OD, PhD, FAAO
Professor and Interim Director
Thomas F. Freddo, OD, PhD, FAAO
Professor and Co-Editor, Optometry Rounds
Contributing Faculty Authors:
Sarah MacIver, OD, FAAO
Clinical Lecturer
C. Lisa Prokopich, OD, MSc
Clinical Lecturer
Michelle Steenbakkers-Woolley, OD, FAAO
Clinical Lecturer
Why Treat Dry Eye Syndrome (DES)?
Based on demographics alone, up to 35% of the population is affected by DES.1 Its significance for
patients and impact on quality of life (QOL) are immutable, as is its relationship with other chronic systemic diseases (eg, Sjögren syndrome). Because optometrists have an array of therapeutic options (ie,
refractive care, topical and oral agents, lacrimal occlusive therapy) to manage all aspects of DES, along
with the insight to engage other healthcare practitioners, they are best placed to address this disease. In
most provinces, optometrists still face therapeutic law limitations with some aspects of contemporary
DES management; however, most of these can be overcome with appropriate interprofessional collaboration and communication. To effectively manage DES patients, it is important to understand the recent
changes in our understanding of its pathophysiology. These changes have affected the clinical categories
of DES and, hence, the management approach is now targeted at treating its underlying causes.
The Lacrimal Functional Unit (LFU) and a New Definition of DES
The LFU is composed of the main and accessory lacrimal glands, the ocular surface (conjunctiva,
cornea, and meibomian gland orifices), and the interconnecting innervations consisting of sensory input
from the trigeminal nerve and stimulation of the accessory and main lacrimal glands by efferent secretomotor neurons.2,3 The purpose of the LFU is to regulate the major components of the tear film to preserve the integrity of the ocular surface. Goblet cells and conjunctival epithelial cells contribute to the
LFU, providing protection to the ocular surface due to their mucin-secreting abilities and production and
release of antibacterial agents and immunoglobulins. Damage to any component of the LFU can disrupt
the reflex pathway and destabilize the tear film, leading to disease of the ocular surface.1,3
In 1995, the National Eye Institute established a global definition for DES and identified damage to
the ocular surface as the main contributor to its symptoms of discomfort. This view was held for over a
decade until it became evident that additional key underlying factors – hyperosmolarity and inflammation – contribute to the signs and symptoms of DES and needed to be added to the definition.4
École d’Optométrie
School Administration:
Christian Casanova, PhD
Director and Professor
Neurophysiology and Imaging
Danielle de Guise, OD, MSc
Associate Director of Cycle 1 Studies
Binocular Vision and Orthoptics
Jocelyn Faubert, PhD, FAAO
Associate Director of Research and Advanced Studies
Professor, Psychophysiology and Visual Perception
Jacques Gresset, OD, PhD, FAAO
Secretary and Professor
Epidemiology and Low Vision
Editorial Committee:
Jean-François Bouchard, BPharm, PhD
Associate Professor, Neuropharmacology
Pierre Forcier, OD, MSc
Associate Professor, Ocular Health
Langis Michaud, OD, MSc, FAAO (Dipl.)
Associate Professor, Contact Lenses
Co-Editor, Optometry Rounds
Judith Renaud, OD, MSc
Assistant Professor, Low Vision
Redefining dry eye
In 2007, the Dry Eye WorkShop (DEWS) redefined DES as 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.”2 This definition specifically excluded the aqueous deficient
dry eye (ADDE) and evaporative dry eye (EDE) distinctions, although these are retained in the pathogenic classification of DES.2 While the ability to identify these 2 components is helpful in management
Available online at www.optometryrounds.ca
University of Waterloo
School of Optometry & Vision Science
200 University Avenue West, Waterloo, ON N2L 3G1
Université de Montréal
École d’Optométrie
3744 Jean-Brillant, Montreal, QC H3T 1P1
The editorial content of Optometry Rounds is determined
solely by the School of Optometry & Vision Science,
University of Waterloo, and the School of Optometry,
University of Montreal.
decisions, the clinical crux is that they are frequently seen concomitantly and, therefore, it is difficult to distinguish the relative contribution of each. Indeed, one may induce the other,
due to the initiation of the inflammatory cascade.
associated with dry eye disease(s).2,12,13 While increasing age
and female gender are 2 of the most significant risk factors for
developing DES, the full list of predisposing risk factors is
extensive (Table 1).2,14-23
The game changer: inflammation
Diagnosing DES During a Routine Eye Examination
The pathophysiology of DES is complex and multifactorial. A variety of factors may initiate the dry eye cycle by targeting one of the structures in the LFU. Lacrimal dysfunction
may occur from Sjögren syndrome or other systemic conditions affecting the lacrimal glands (eg, sarcoidosis), thus leading to ADDE. It may also be caused by meibomian gland
dysfunction (MGD), inadequate blink, or other causes of
EDE. The common findings in all of these etiologies are tear
film instability and hyperosmolarity.2,5-7 In ADDE, there is an
overall decrease in tear clearance that leads to hyperosmolarity.8,9 In EDE, hyperosmolarity is triggered by local drying and
exposure of the ocular surface.2,5 Recent evidence has identified an intrinsic inflammatory marker – the human leukocyte
antigen (HLA)-DR – in DES patients with and without
Sjögren syndrome.9-11
Following activation of the inflammatory cascade, apoptosis is initiated in the ocular surface epithelial cells, including
the goblet cells. Goblet cell loss and corresponding reduction
in the gel mucin, MUC5Ac, has been identified as a feature in
every form of DES.5,7,13 Apoptosis of the surface epithelial cells
leads to further tear film instability. This, in turn, leads to an
increase in hyperosmolarity, progression of the inflammatory
cascade, and further destruction of the ocular surface.1 This
“core mechanism” of DES is illustrated in Figure 1. Ideally,
DES management should focus at arresting this vicious cycle,
allowing a reduction in inflammation and healing of the ocular surface.5
Ideally, all patients should be assessed for risk of DES at
their annual eye examination as per the chronic disease
model.1 While several tests are available to aid in the diagnosis, none is considered accurate and repeatable enough to be a
stand-alone or gold standard. Furthermore, there are no uniform criteria for the diagnosis of the spectrum of dry eye diseases.13 Regardless, tests continue to have important clinical
value in determining the presence and severity of DES
(Table 2). This sequence of tests adds a minimal amount of
time to the total eye examination (Figure 2), but may provide
invaluable information in identifying which patients are in
need of therapeutic intervention.
Many dry eye questionnaires are available to help screen
patients with dry eye symptoms. Such questionnaires are
invaluable in identifying, diagnosing, and monitoring a
patient’s symptoms, and optometrists should choose one with
which they are comfortable.
Once a patient is identified as having DES, diagnostic tests
should be included in the routine eye examination. When
there are symptoms, the initial dry eye diagnosis is made at
the slit lamp, with assessment of the lid margins, tear film
quality, tear meniscus height, and quality of the meibomian
gland excretions in white light.13
Once dry eye symptoms or signs are identified, a minimum
number of diagnostic tests should be added to the annual routine eye check-up. Phenol red thread testing of tear volume is
cost-effective and takes only 15-30 seconds per eye. This is an
easy and effective way to identify patients with ADDE, either as
Who is at Risk for DES?
Many factors play a part in the development of DES. The
demographic of the postmenopausal woman is frequently
Figure 1: The “core mechanism” of dry eye syndrome (DES)
Table 1: Risk factors for DES
• Environmental conditions14
– Low-humidity environment including air conditioning,
air travel, wind velocity, or other artificial environments
• Contact lens wear15-17
• Physiological disposition2,18-20
– Low blink rate, often associated with extended
computer use, reading, or television viewing
– Larger palpebral aperture
– Proptosis
Tear film
instability
Goblet cell
and surface
epithelial
destruction
Increased
osmolarity
Inflammation
Apoptosis
(includes IL-1α,
IL-1β TNF-α,
MMP-9)
Adapted from the 2007 International Dry Eye WorkShop (DEWS) report2
IL = interleukin; TNF = tumour necrosis factor;
MMP = matrix metalloproteinase
2
• Systemic conditions2,19-22
– Any systemic condition that results in a hormonal
imbalance, autoimmune conditions, or destruction of
lacrimal or meibomian gland; eg, sarcoidosis
– Thyroid disease
– Diabetes mellitus
– Autoimmune conditions; eg, rheumatoid arthritis,
systemic lupus erythematosus, and fibromyalgia
• Systemic medications2
– Antihistamines, systemic beta-blockers, antispasmodics,
diuretics, and antidepressants
• Topical medications16-19,23
– Benzalkonium chloride
Table 2: Common clinical tests used to diagnosis and monitor DES
Test
ADDE/EDE
24
Symptom
questionnaires
eg, McMonnies, DEQ,
OSDI,26 CDEQ27
Tear quantity
25
Clinical value
“Normal” measurement
ADDE / EDE
Symptoms graded at visit can be
compared to baseline during
management
Differs for each test
Phenol red thread test28-30
ADDE
Index of tear volume
Schirmer test without
anesthesia12,19
ADDE
Index of tear secretion helpful for
Sjögren diagnosis
Tear meniscus height
(estimate height with
adjustable vertical slit-lamp
beam)14
ADDE
Aqueous secretion
Ocular surface
damage31,32
Sodium fluorescein (SF) dye
(with Wratten barrier filter
#12), lissamine green (LG),
rose bengal (RB)
ADDE/EDE
SF stains/pools in intercellular spaces
LG, RB stain cells with membrane
damage
Grade according to
density/location
Pattern: diffuse with
coalescent patches
(Figure 4)
MGD
Lid margin evaluation
(clinical features)33-35
EDE
Posterior displacement of gland
orifices, lid notching, MG atrophy,
telangiectasia
Grade according to
severity: mild, moderate,
severe
MG expression20,33,35
EDE
Number of expressible glands, quality
of secretion
See Figures 5 and 6
Tear film quality
Slit-lamp biomicroscopy
(including specular
reflection)14
ADDE/EDE
Look for debris, saponification
(Figure 3), oil
Grade according to
findings
Tear film
osmolarity
Commercially available
system
ADDE/EDE
Proposed “gold standard” for
diagnosis
Tear film stability
Tear break up time
(fluorescein dye instillation)18
EDE
Fast and accurate test good sensitivity
(83%) and specificity (85%)
≤12 mm in 15 seconds
≤5 mm in 5 minutes
≤0.25 mm clinically
estimated as normal,
excessive, or shallow
≤316 mOsm/L
<10 seconds
ADDE = aqueous deficient dry eye; EDE = evaporative dry eye; DEQ = Dry Eye Questionnaire; OSDI = Ocular Surface Disease Index;
CDEQ = Canadian Dry Eye Questionnaire; MGD = meibomian gland dysfunction
an isolated entity or as a comorbidity with MGD.28-30 The typical clinical appearance of MGD – “the pink eyeliner sign” (Figure 3) – consists of hyperemic and telangiectatic lid margins,
along with early notching, posterior displacement of the meibomian gland orifices, and thick, toothpaste-like glandular
expression. The next steps include assessment of tear instability
and ocular surface damage to both the cornea and conjunctiva
using fluorescein dye and a yellow (Wratten #12) barrier filter.
Ideally, damage to the conjunctival surface is evaluated with
rose bengal or lissamine green staining; however, conjunctival
staining can be graded using fluorescein alone and is a reasonable starting point.13,31,32 The pattern of the staining is telling in
Figure 2: Sequence and timing of an initial dry eye
assessment (4-5 minutes)
Questionnaire
Slit-lamp of
lids and
ocular
surface
(1.5 min)
Phenol red
thread (15s
per eye,
repeated
once)
(1 min)
Tear
Break-up
Time
(30 sec)
terms of DES severity and type. Corneal staining is often central
in ADDE, inferior along the lid margin in EDE, and becomes
coalescent in density as inflammation progresses.13,32
Tear film osmolarity was identified by the DEWS13 as the
most important potential test for diagnosing DES. There is
considerable value in assessing a parameter that is directly
involved in the mechanism of dry eye.
MG expression. According to both the DEWS13 and the
International Workshop on MGD,33 MGD is the leading cause
Figure 3: MGD. Note the “pink eyeliner sign” from
hyperemic and telangiectatic lid margins, early notching,
posterior displacement of the gland orifices, and thick,
toothpaste-like glandular expression.
Meibomian
gland
expression
(1-2 min)
3
of DES worldwide. This development has altered the diagnostic paradigm for DES to focus on assessing the ease and quality of meibomian expression in every dry eye patient.34-36 All
glands should be expressed with digital pressure for 10–15
seconds in the nasal, central, and temporal section of the
lower lid. An assessment should be made of the quality of the
expressed oil. There appears to be more clinical utility in
assessing the expressibility of the nasal and central glands
since damage to the nasal glands causes more MGD symptoms. Figure 5 illustrates the expression of glands in a symptomatic patient with nonobvious MGD. Figure 6 illustrates tear
film saponification noted following MG expression.
To help manually express the glands, patients may use hot
compresses (see below) or MG expressors. These latter tools
have been shown to be effective in expressing chronically
impacted glands.32
Figure 4: Coalesced superficial punctate keratitis from a
patient with Sjögren syndrome. The coalescent pattern is a
characteristic sign indicating severe inflammation is present
on the ocular surface.
Management: Conventional Versus Contemporary
Evaluation and management of the patient diagnosed
with DES should begin with assessing the severity
(Table 3). 13,14,37-39 The goals of treatment should be geared
towards ensuring that the patient’s symptoms are improved
and that there is no risk of vision loss.14,40 Optometric physicians should be aware that the various guidelines are recommendations and that each patient presents with a unique set
of symptoms, signs, and circumstances. There is no cookbook approach to management; therefore, attention should
be paid to both determining the etiology of the dry eye and
targeting the underlying causes of the disease, inflammation
and tear hyperosmolarity.
First-line Management
The typical first line of treatment is lubricating agents –
eye drops and gels, often misnamed “artificial tears” – and
general lid hygiene to improve the health of the lids and
meibomian glands.14 Lubrication and lid hygiene should be
considered as minimum baseline therapy for all DES
patients.
Table 3: Dry eye severity: a clinical reference guide
Severity level
1
2
3
Mild and/or episodic,
occurring under
environmental stress
Moderate episodic or
chronic, stress or no
stress
Severe, frequent or
constant
Occurs without stress
Severe and disabling or
constant
Visual symptoms
None or episodic, mild
fatigue
Annoying and/or
activity-limiting episodic
Annoying, chronic,
and/or constant,
limiting activity
Annoying, chronic and/or
constant limiting activity
Conjunctival injection
None to mild
None to mild
+/–
+/++
Conjunctival staining
None to mild
Variable
Moderate to marked
Marked
Corneal staining
(severity/location)
None to mild
Variable
Marked central or
peripheral (MGD)
Severe punctate erosions
Corneal/
tear film signs
None to mild
Mild debris, decreased
meniscus
Filamentary keratitis,
mucus clumping,
increased tear debris
Filamentary keratitis, mucus
clumping, increased tear
debris, ulceration
MGD
Minimally altered
expressibility and
secretion quality
(meibum: cloudy)
Mildly altered
expressibility and
secretion quality
(meibum: cloudy with
particles)
Moderately altered
expressibility and
secretion quality
(meibum: inspissated,
toothpaste like)
Tear break up time
Variable
≤10 seconds
Schirmer score
(mm/5 min)
Variable
≤10 mm
≤5 seconds
Severely altered
expressibility and secretion
quality
May include: Trichiasis,
keratinization,
symblepharon
Phenol red thread test
Variable
≤15 mm
≤10 mm
≤5 mm
Adapted from Behrens A et al,39 and International Workshop on Meibomian Gland Dysfunction.33
4
4
Discomfort, severity
and frequency
Immediate
≤2 mm
≤5 mm
Figure 5: Expression of meibomian glands in a symptomatic
patient with non-obvious MGD. Note the thick, toothpastelike meibum secretion.
Lid hygiene
Lid hygiene includes hot compresses, massage, and lid
scrubs. A warm (40°C) towel compress applied for 5 minutes
was shown to increase the tear film lipid layer thickness by up
to 80%.41 Combining compresses with firm massage of the
eyelids can be an effective means of meibum expression; however, compresses may heat only the anterior portion of the
glands and may not reach pathologically compacted glands
posteriorly.
Lubricating agents
Lubricating agents attempt to mimic natural tear composition by containing lipids, aqueous, and mucin components. 10 Various formulations have been found to reduce
symptoms and provide objective benefits such as increasing
lipid layer thickness and tear volume; 42-47 however, these
agents rarely result in the elimination of symptoms. 14,40
According to the DEWS,14 the ideal lubricant would contain
potassium, bicarbonate, and other electrolytes, be free of
preservatives, have a neutral to slightly alkalinic pH, and contain a polymeric system to prolong retention time. The International Workshop on MGD 35 stated that lubricants with
higher viscosities are associated with improved results in the
management of DES than lower-viscosity preparations, and
that lipid supplements have been shown in clinical studies to
improve symptoms and signs of MGD, possibly further to
improvement in tear film stability.
W-3 fatty acid supplementation
W-3 fatty acid supplementation should also be initiated at
the onset of DES, especially if MGD is present, because of its
impact on the lipid layer.10 W-3 and W-6 fatty acids mediate
inflammation in DES.48-50 The importance of W-3 use in dry
eye disease and MGD is 3-fold: restoration of the lipid layer,
decreased inflammation and apoptosis, and increased tear
secretion.48,51 W-3 fatty acids, including eicosapentaenoic acid
(EPA), docosahexaenoic acid, and a-linolenic acid, mediate
anti-inflammatory factors, while W-6 fatty acids
(ie, g-linolenic acid and arachidonic acid) produce proinflammatory factors.51 Therefore, maintaining a balance between
Figure 6: Saponification in the tear film that is secreted
following meibomian gland expression.
the 2 fatty acids is essential to achieve an optimal overall
inflammatory state. W-3 dietary supplementation is recommended since it is often lacking in the diet, while W-6 supplementation is less important.51
Core Management
In addition to solely targeting dry eye symptoms, the
optometrist should also introduce appropriate core management strategies that target the underlying causes of DES. Specific core management strategies are listed in Table 4. The
International Workshop on MGD identified a group of
patients that are distinct from the severity scale; this group was
designated as having MGD “plus” disease since they have MGD
in conjunction with another type of ocular surface disease,
including anterior blepharitis.40 This group of patients typically requires more aggressive management from the onset.
A decade ago, the steroid class of medications was being
prescribed with trepidation in DES, especially in eyes with a
compromised cornea. The notion of delayed epithelial wound
healing along with other adverse effects associated with topical steroids superseded the potential of these agents, as well as
other medications in the anti-inflammatory category. To some
extent, these old adages remain, although the plethora of
research on the inflammatory nature of DES and associated
ocular surface disease supports the incorporation of these
medications earlier and more aggressively in the management
protocol.10,52-56 It is known that DES, regardless of its etiology,
proceeds in a vicious cycle and unless treatment targets part of
the cycle, it will progress. Hyperosmolarity, and therefore
inflammation, has been identified as the main cause of all
forms of DES and it ensures the perpetuation of this cycle,
regardless of the cause. A topical anti-inflammatory medication targets the production of inflammatory cytokines, thus
preventing further damage to goblet cells and further tear film
instability.5 Topical corticosteroids, topical cyclosporine A,
and/or oral tetracycline should be considered early in management protocols and part of core management.
Topical corticosteroids
Topical corticosteroids have been shown to be effective in
the treatment of DES. Their mechanism of action involves
5
Table 4: Common treatments for dry eye syndrome14
Minimum
baseline therapy
(to be initiated
on all patients
regardless of
severity)
Hot compresses
Lid scrubs and massage
Lubricating agents (“artificial tears”)
Drops, ointment, gel
Preservative and preservative-free
Lipid-containing formulations
W-3 fatty acid supplementation
Core
management
strategies
(To be used in
conjunction with
above baseline
therapy)
Antiinflammatory
Osmolarity
reduction
Anti-Inflammatory Therapy
Topical corticosteroids
Initiate soft /lower-potency steroid (eg, loteprednol
etabonatea 0.5% ophthalmic suspension < fluorometholone
0.1% ophthalmic suspension < prednisolone phosphate
1.0% ophthalmic solution)
Topical corticosteroids
Cyclosporin A 0.05%
ophthalmic emulsion
Oral tetracyclines
• 1 gt qd for 2–4 weeks, and assess efficacy
• If good response, 1 gt bid for 2–4 weeks
Topical cyclosporine A
Lacrimal occlusion
Autologous serum
Secretagogues
Initiate cyclosporine A 0.005% ophthalmic emulsion
• 1 gt bid indefinitely
Protective
Moisture chamber
lenses
Scleral contact lenses
• Can be initiated concomitantly with a corticosteroid;
taper the corticosteroid dose and discontinue over
2–4 weeks
Anti-infective
Topical antibiotics for
anterior blepharitis
Oral tetracyclinesb
inhibition of cytokine production, decreased synthesis of
matrix metalloproteinases (MMPs) and arachidonic acid
derivatives, and induced lymphocyte apoptosis. 53,57,58 The
long-term use of topical corticosteroids for DES is controversial because of the potential risk of posterior subcapsular
cataract development, a rise in intraocular pressure, and
development of glaucoma and delayed wound healing; 40,58
however, studies showed promising results for the use of these
agents in dry eye that support their short-term use.59,60 Less
potent topical steroids are being evaluated for their utility in
dry eye management. Topical fluorometholone acetate and
the soft topical steroid loteprednol etabonate (0.5%) have
been shown to be efficacious with a reduction in the incidence
of elevated intraocular pressure.58,61
Topical corticosteroids can be used as first-line treatment,
before the occurrence of damage, or secondary to inadequate
treatment with lubricating agents and/or hot compresses.
Most patients with DES of severity ≥2 report immediate
symptom relief.51
Topical cyclosporine A
Cyclosporine A 0.05% ophthalmic emulsion was
approved by Health Canada in 2010 for the treatment of moderate to moderately severe (DEWS level 2-3) ADDE.62 Oral
cyclosporine A was initially used as systemic immunosuppressive therapy following organ transplantation; however, it
showed an increase in tear lacrimation.23 Topical ophthalmological application results in no measureable levels of
cyclosporine in the bloodstream, and thus is considered to be
a local anti-inflammatory agent with local immunomodulatory, but not immunosuppressant, activity.62 Cyclosporine A is
most effective in individuals with suppressed tear production
associated with inflammation. It decreases inflammatory
markers and therefore inflammation on the ocular surface.
Compliance with cyclosporine A is not always optimal, which
can also reduce its effectiveness. In general, a compliant
patient will experience improvement in approximately 6–8
6
PRACTICE PEARLS
Initiate oral tetracycline derivative (eg, doxycycline or
minocycline)
• 20–40 mg daily for ~3 monthsc
a
Loteprednol etabonate is indicated by Health Canada for use postcataract surgery;
Not indicated by Health Canada for the treatment of ocular
inflammation;
c
The optimal duration of therapy with doxycycline or minocycline has
not been established40
b
weeks, and there may be a delay between clinical evidence of
benefit and patient reporting of improvement. Compliance
can be improved with patient education and application of a
topical corticosteroid.
Oral tetracyclines
Inflammation in MGD is generated due to excessive lipase
activation and changes in lipid composition that lead to a
destabilized tear film.5,33 Macrolide antibiotics contain antiinfective, distinct immunomodulatory, and anti-inflammatory
properties. 10,33,40 Tetracyclines are not indicated by Health
Canada for the reduction of ocular inflammation, but their use
for this condition is supported by several guidelines, particularly for ocular rosacea.14,27,40 Reduction of inflammation may
be achieved at a lower dose than that routinely prescribed for
antimicrobial use. The exact mechanism behind the antiinflammatory component is unknown, but clinical studies
support their role in decreasing both lipases and MMP-8.40,63,64
The tetracycline derivatives doxycycline and minocycline are
more lipophilic than tetracyclines and, therefore, have better
potential to penetrate into the ocular tissues at lower concentrations, including the lids, meibomian glands, and the
tears.40,65,66 Doxycycline and minocycline can be effective as
anti-inflammatories at 20–40 mg daily, as opposed to their typical antibiotic dose of 50–100 mg once or twice daily. Duration
of therapy is usually 3 months; however, an optimal time
course has not been proven.40 Common adverse effects of the
oral medication include sun sensitivity and gastrointestinal
upset if taken on an empty stomach. Unlike oral tetracyclines,
oral doxycycline can be taken with food and milk.67 Oral tetracyclines interact with a number of different medications so it is
important to be alert for any potential drug-drug interactions
with the patient’s list of medications.
Other Therapies
Secretagogues
The muscarinic agonist pilocarpine has been found to be
effective in increasing tear and saliva production in individuals with Sjögren syndrome.68 However, this agent is associated
with systemic cholinergic adverse effects, such as excessive
perspiration (40%), chill (20%), nausea (13%), hypersalivation (13%), and intestinal cramping (7%).
Moisture-retaining eyewear
Eyewear such as moisture chamber lenses and hydrophilic
bandage or scleral contact lenses improve ocular hydration; the
latter also act as a barrier between the eye and lid. The primary
complication associated with bandage contact lenses is infection.
Conclusion
Although DES is a chronic and, at times, recalcitrant disease, its management can be rewarding for both patients and
practitioners. Earlier and more accurate identification of
patients with, or at risk of, DES will minimize reductions in
their QOL. Minimum baseline therapy entails lid hygiene, eye
lubrication, and W-3 fatty acid supplementation. More severe
cases of DES often require additional interventions. As hyperosmolarity and inflammation are at the core of dry eye, core
management strategies that target these conditions should be
considered concomitantly with conventional treatments.
While management strategies are always dependent on the
individual patient’s symptoms, signs, circumstances, and
adherence to therapy, practitioners are encouraged to consider
anti-inflammatory options early in the treatment regimen.
Dr. MacIver is a Clinical Lecturer at the University of Waterloo,
School of Optometry and Vision Science. Dr. SteenbakkersWoolley is a Clinical Lecturer at the University of Waterloo,
School of Optometry and Vision Science. Dr. Prokopich is a
Clinical Professor, University of Waterloo, School of Optometry
and Vision Science, Waterloo, Ontario.
References:
1. Barr VJ, Robinson S, Marin-Link B, et al. The expanded chronic care
model: an integration of concepts and strategies from population health
promotion and the chronic care model. Hosp Q. 2003;7(1):73-82.
2. The definition and classification of dry eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye
Workshop (2007). Ocul Surf. 2007;5(2):75-92.
3. Stern ME, Gao J, Siemasko K, Beuerman RW, Pflugfelder SC. The role
of the lacrimal functional unit in the pathophysiology of dry eye. Exp
Eye Res. 2004;78(3):409-416.
4. Lemp MA. Report of the National Eye Institute/Industry Workshop on
Clinical Trials in Dry Eye. CLAO J. 1995;21(4):221-232.
5. Baudouin C. A new approach for better comprehension of disease of
the ocular surface. J Fr Ophthalmol. 2007;30(3):239-246.
6. Bron AJ, Tiffany JM. The contribution of meibomian disease to dry
eye. Ocul Surf. 2004;2(2):149-164.
7. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC.
The pathology of dry eye; the interaction between the ocular surface
and lacrimal glands. Cornea. 1998;17(6):584-589.
8. Pflugfelder SC, Solomon A, Dursun DLi DQ. Dry eye and delayed tear
clearance: “a call to arms.” Adv Exp Med Biol. 2002;506(Pt B):739-743.
9. Stern ME, Gao J, Schwalb TA, Ngo M, Tieu DD, Chan CC,et al. Conjunctival T-cell subpopulation in Sjögren’s and non-Sjögren’s patients
with dry eye. Invest Ophthalmol Vis Sci. 2002;43(8):2609-2614.
10. Luo L, Li DQ, Doshi A, Farley W, Corrales RM, Pflugfelder SC. Experimental dry eye stimulates production of inflammatory cytokines and
MMP-9 and activates MAPK signaling pathways on the ocular surface.
Invest Ophthalmol Vis Sci. 2004;45(12):4293-4301.
11. 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. IOVS. 2001;42(10):2283-2292.
12. Mantelli F, Moretti C, Micera A, Bonini S. Conjunctival mucin deficiency in complete androgen insensitivity syndrome (CAIS). Graefes
Arch Clin Exp Ophthalmol. 2007;245(6):899-902.
13. Methodologies to diagnose and monitor dry eye disease: Report of the
Diagnostic Methodology Subcommittee of the International Dry Eye
Workshop (2007). Ocul Surf. 2007;5(2):108-152.
14. Management and therapy of dry eye disease: Report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):163-178.
15. Schlanger JL. A study of contact lens failures. J Am Optom Assoc.
1993;64(3):220-224.
16. Gilbard JP, Rossi SR, Heyda KG. Ophthalmic solutions, the ocular surface, and a unique therapeutic artificial tear formulation. Am J Ophthalmol. 1989;107(4):348-355.
17. Nichols JJ, Sinnott LT. Tear film, contact lens, and patient-related factors associated with contact lens-related dry eye. Invest Ophthalmol Vis
Sci. 2006;47(4):1319-1328.
18. Schlote T, Kadner G, Freudenthaler. Marked reduction and distinct
patterns of eye blinking in patients with moderately dry eyes during
video display terminal use. Graefe’s Arch Clin Exp Ophthalmol.
2004;242(4):306-312.
19. Cermak JM, Krenzer KL, Sullivan RM, Dana MR, Sullivan DA. Is complete androgen insensitivity syndrome associated with alterations in the
meibomian gland and ocular surface? Cornea. 2003;22(16):516-521.
20. Afonso A, Monroy D, Stern M, Feuer WJ, Tseng SC, Pflugfelder SC.
Correlation of tear Fluorescein clearance and Schirmer test scores with
ocular irritation symptoms. Ophthalmology. 1999;106(4):803-810.
21. Módulo CM, Jorge AG, Dias AC, et al. Influence of insulin treatment
on the lacrimal gland and ocular surface in diabetic rats. Endocrine.
2009;36(1):161-168.
22. Manaviat MR, Rashidi M, Afkhami-Ardekani M, et al. Prevalence of
dry eye syndrome and diabetic retinopathy in type 2 diabetic patients.
BMC Ophthalmol. 2008;8:10.
23. Abietz J, Bruce A. The conjunctival epithelium in dry eye subtypes:
Effect of preserved and non-preserved topical treatments. Curr Eye
Res. 2001;22(1):8-18.
24. McMonnies CW. Key questions in a dry eye history. J Am Optometric
Assoc. 1986;57(7):512-517.
25. Begley CG, Caffery B, Nichols K, Mitchell GL, Chalmers R; DREI study
group: results of a dry eye questionnaire from optometric practices in
North America. Adv Exp Med Biol. 2002;506(Pt B):1009-1016.
26. Miller KL, Walt JG, Mink DR, et al. Minimal clinically important difference for the Ocular Surface Disease Index. Arch Ophthalmol.
2010;128(1):94-101.
27. Jackson WB. Management of dysfunctional tear syndrome: a Canadian
consensus. Can J Ophthalmol. 2009;44(4):385-394.
28. Nichols KK, Nichols JJ, Lynn Mitchell G. The relation between tear
film tests in patients with dry eye disease. Ophthalmic Physiol Opt.
2003;23(16):553-560.
29. Labetoulle M, Mariette X, Joyeau L, Baudouin C, et al. The phenol red
thread first results for the assessment of the cut off value for ocular
sicca syndrome. J Fr Ophthalmol. 2002;25(7):674-680.
30. Patel S, Farrell J, Blades KJ, Grierson DJ. The value of a phenol red
impregnated thread for differentiating between the aqueous and nonaqueous deficient dry eye. Ophthalmic Physiol Opt. 1998;18(6):471-476.
31. Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003;22(7):640-650.
7
32. Nichols, KK, Mitchell GL, Zadnik K.The repeatability of clinical measurements of dry eye. Cornea. 2004;23(3):272-285.
33. Tomlinson A, Bron AJ, Korb DR, et al. The International Workshop on
Meibomian Gland Dysfunction: Report of the Diagnosis Subcommittee. Invest Ophthalmol Vis Sci. 2011;52(4):2006-2049.
34. Foulks G, Brown AJ. A clinical description of meibomian gland dysfunction. Ocul Surf. 2003;1(3)107-126.
35. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The International
Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Anatomy, Physiology, and Pathophysiology of the Meibomian Gland. Invest Ophthalmol Vis Sci. 2011;52(4):1938-1978.
36. Carlson A. A new paradigm for treating dry eye patients. Advanced
Ocular Care. October 2010. Available at: http://bmctoday.net/
advancedocularcare/2010/10/article.asp?f=a-new-paradigm-fortreating-dry-eye-patients. Accessed on November 28, 2012.
37. The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf.
2007;5(2):93-107.
38. Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK.
The International Workshop on Meibomian Gland Dysfunction: Report
of the Subcommittee on the Epidemiology of, and Associated Risk Factors for MGD. Invest Ophthalmol Vis Sci. 2011;52(4):1994-2005.
39. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi
approach to treatment recommendations. Cornea. 2006;25(8):900-907.
40. Geerling G, Tauber J, Baudouin C, et al. The International Workshop
on Meibomian Gland Dysfunction: Report of the subcommittee on
Management and Treatment of Meibomian Gland Dysfunction. Invest
Ophthalmol Vis Sci. 2011;52(4):2050-2064.
41. Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction. Eye Contact Lens. 2003;29(2):96-99.
42. Lee SY, Tong L. Lipid-containing lubricants for dry eye: a systematic
review. Optom Vis Sci. 2012;89(11):1654-1661.
43. Petricek I, Berta A, Higazy MT, Németh J, Prost ME. Hydroxypropylguar gellable lubricant eye drops for dry eye treatment. Expert Opin
Pharmacother. 2008;9(8):1431-1436.
44. Doughty MJ, Glavine S. Efficacy of different dry eye treatments with
artificial tears or ocular lubricants: a systematic review. Ophthalmic
Physiol Opt. 2009;29(6):573-583.
45. Davitt WF, Bloomenstein M, Christensen M, Martin AE. Efficacy in
patients with dry eye after treatment with a new lubricant eye drop
formulation. J Ocul Pharmacol Ther. 2010;26(4):347-353.
46. Scaffidi RC, Korb DR. Comparison of the efficacy of two lipid emulsion eyedrops in increasing tear film lipid layer thickness. Eye Contact
Lens. 2007;33(1):38-44.
47. Garcia-Lázaro S, Madrid-Costa D, Ferrer-Blasco T, Montés-Micó R,
Cerviño A. OCT for assessing artificial tears effectiveness in contact
lens wearers. Optom Vis Sci. 2012;89(1):E62-E69.
48. Roncone M, Bartlett H, Eperjesi OF. Essential fatty acids for dry eye:
A review. Cont Lens Anterior Eye. 2010;33(2):49-54.
49. Miljanovic B, Trivedi KA, Dana MR, Gilbard JP, Buring JE, Schaumberg DA. Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr. 2005;
82(4):887-93.
50. Jackson MA, Burrel K, Gaddie IB, et al. Efficacy of a new prescriptiononly medical food supplement in alleviating signs and symptoms of
dry eye with or without concomitant cyclosporine A. Clin Ophthalmol.
2011; 5-1201-6
51. Macsai, M. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (An AOS thesis). Trans Am Ophthalmol Soc. 2008; 106:336-356.
52. Pflugfelder SC. Anti-inflammatory therapy for dry eye. Am J Ophthalmol. 2004;137(2):337-342.
53. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and
doxycycline suppress MMP-9 and inflammatory cytokine expression,
MAPK activation in the corneal epithelium in experimental dry eye.
Exp Eye Res. 2006;83(3):526-535.
54. Yang CQ, Sun W, Gu YS. A clinical study of the efficacy of topical corticosteroids on dry eye. J Zhejiang Univ Sci B. 2006;7(8):675-678.
55. Zeligs MA. Dehydroepiandrosterone therapy for the treatment of dry
eye disorders. Int Patent. W O94/04155, 1994.
56. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine.
Immunopharmacology. 2000;47(2-3):119-125.
57. Li DQ, Luo L, Chen Z, Kim HS, Song XJ, Pflugfelder SC. Doxycycline
inhibits TGF-beta1-induced MMP-9 via Smad and MAPK pathways in
human corneal epithelial cells. Invest Ophthalmol Vis Sci. 2005;46(13):
840-848.
58. Sendrowski DP, Jannus SD, Semes LP, et al. Anti-inflammatory drugs.
In: Bartlett JD. Clinical Ocular Pharmacology, 5th ed. St. Louis (MO):
Butterworth-Heinemann; 2008:221-244.
59. Hong S, Kim T, Chung SH, Kim EK, Seo KY. Recurrence after topical
nonpreserved methylprednisolone therapy for keratoconjunctivitis
sicca in Sjogren’s syndrome. J Ocul Pharmacol Ther. 2007;23(1):78-82.
60. Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone
therapy for keratoconjunctivitis sicca in Sjogren syndrome. Ophthalmology. 1999;106(14):811-816.
61. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double
masked, placebo-controlled, multicenter comparison of loteprednol
etabonate ophthalmic suspension, 0.5%, and placebo for treatment of
keratoconjunctivitis sicca in patients with delayed tear clearance. Am J
Ophthalmol. 2004;138(3):444-457.
62. Allergan Inc. Restasis® (cyclosporine ophthalmic emulsion 0.05%)
Product Monograph. Date of revision: August 16, 2010.
63. Kari O, Määttä M, Tervahartiala T, et al. Tear fluid levels of MMP-8 are
elevated in ocular rosacea: treatment effect of oral doxycycline. Graefes
Arch Clin Exp Ophthalmol. 2006;244(8):957-962.
64. Shine WE, McCulley JP, Pandya AG. Minocycline effect on meibomian
gland lipids in meibomianitis patients. Exp Eye Res. 2003;76(4):417-420.
65. Souchier M, Joffre C, Grégoire S, et al. Changes in meibomian fatty
acids and clinical signs in patients with meibomian gland dysfunction
after minocycline treatment. Br J Ophthalmol. 2008;92(6):819-822.
66. Hoeprich PD, Warshauer DM. Entry of four tetracyclines into saliva
and tears. Antimicrob Agents Chemother. 1974;5(3):330-336.
67. Pfizer Canada Inc. Vibramycin* (doxycycline hyclate capsules and
tablets) Product Monograph. Date of revision: March 30, 2010.
68. Aragona P, Di Pietro R, Spinella R, Mobrici M. Conjunctival epithelium improvement after systemic pilocarpine in patients with Sjogren’s
syndrome. Br J Ophthalmol. 2006;90(2):166-170.
The authors report that they have no financial disclosures or
financial interest in publishing the content of this article.
A Partnership for Excellence in Continuing Optometry Education
Optometry Rounds is made possible through independent sponsorships from
Alcon Canada and Novartis Pharmaceuticals Canada Inc.
© 2013 School of Optometry & Vision Science, University of Waterloo, and School of Optometry, University of Montreal, which are solely responsible for the contents. The opinions expressed
in this publication do not necessarily reflect those of the publisher or sponsor, but rather are those of the authoring institution based on the available scientific literature. Publisher: SNELL
Medical Communication Inc. in cooperation with the School of Optometry & Vision Science, University of Waterloo, and School of Optometry, University of Montreal. All rights reserved.
The administration of any therapies discussed or referred to in Optometry Rounds should always be consistent with the approved prescribing information Canada.
SNELL
149-002E