Download Dry eye Part 2 Current therapeutic and management options

Dry eye Part 2
Current therapeutic and
management options
Jennifer P. Craig
Introduction
Part 1 of this article reviewed the techniques available to the clinician for evaluating the dry eye. Using a
combination of tests, the aetiology of the dry eye can be best established and the optimal management
strategy selected. In managing dry eye patients, the aim is to improve ocular comfort and quality of life
and, if possible, to facilitate the return of the tear film and ocular surface to their normal, homeostatic
states. A wide variety of treatments exist for dry eye. Depending on the cause and severity, management
may be as simple as educating the patient about environmental modifications which could improve ocular
comfort, or as complex as salivary gland transplantation surgery to preserve vision. This article describes a
number of contemporary strategies available for managing dry eye.
Review of the scientific literature and extensive discussion with dry eye experts led the DEWS
Management and Therapy Subcommittee in 2007 to recommend that clinician base dry eye treatment
selection on disease severity.1 Depending on the outcome of the dry eye evaluation, a dry eye will fall into
one of four disease severity levels. The features of these levels, 1 to 4, are described in Table 1, together
with guidelines for treatment, also tailored to severity. The various treatment recommendations are
described in more detail below, and described in relation to specific tear film deficiencies in Table 2.
Severity
Level 1
Features
Mild or episodic discomfort, often in response to
environmental triggers, with or without visual symptoms.
Mild (if any) signs of conjunctival hyperaemia, ocular
surface staining, lid disease. Tear film stability and
production are variably affected.
Level 2
Moderate discomfort and intermittent visual symptoms with
or without exposure to provocative stimuli, more frequently
exhibit corneal or conjunctival staining. Lid disease may
feature, and tear film stability and production are usually
affected.
Level 3
Frequent or constant symptoms without provocation, and
visual symptoms, which may be activity limiting. Moderate
to marked ocular surface staining, possibly with filamentary
keratitis, tear debris and mucus clumping. Lid disease is
common and tear film stability and production are often
markedly reduced.
Signs and symptoms exhibited. Symptoms often severe,
constant and disabling. Marked conjunctival hyperaemia
and ocular surface staining with filamentary keratitis, mucus
clumping, marked tear film debris and possibly even
ulceration. Marked lid disease often present, associated
with trichiasis, symblepharon and keratinisation. Tear film
break up is immediate and production rates are minimal.
Level 4
Treatment recommendations
Educate about environmental or dietary
modifications.
Modify deleterious systemic medications.
Use of artificial tear supplements, gels and/or
ointments.
Eyelid therapy
If Level 1 treatments jnsufficient, add:
Topical anti-inflammatory treatment
Tetracyclines (lid disease and rosacea)
Punctal plugs
Secretagogues (if available)
Goggles / moisture chamber spectacles
If Level 2 treatments insufficient, add:
Autologous serum
Bandage contact lenses
Permanent punctal occlusion (e.g. cautery)
If Level 3 treatments insufficient, add:
Systemic anti-inflammatory agents
/ immunosuppressives
Surgery:
lid surgery / tarsorrhaphy
mucus membrane, amniotic
membrane or salivary gland transplantation.
Modified from DEWS Management and Therapy. Ocular Surface 2007;5(2):163-178.1
Table 1. Typical signs and symptoms associated with increasing levels of dry eye severity (level 1 = least severe, level 4 = most
severe, together with suggested treatment strategies at each level.
Lifestyle Advice
Patients symptomatic of dry eye can often become more comfortable with minor modifications to their
lifestyle and/or diet. Use of a number of systemic medications, particularly anticholinergics such as
antihistamines and antidepressants can exacerbate dry eye and should be minimised or eliminated if
possible. Similarly desiccating environmental conditions caused by air-conditioning or central heating
should be avoided. Lowering computer monitor height, in order to minimise the exposed interpalpebral
aperture and thereby decrease the evaporative surface area, can reduce the effects of VDU use. (Figures
1(a) and (b)) Full and regular blinking should also be encouraged. Wearing goggles or closely fitting,
wrap-around style, spectacles increases the periocular humidity.2 However, if considered cosmetically
unacceptable by affected individuals, other strategies, such as the placement of a humidifier, or bowls of
water, close to work areas, may help to reduce symptoms.
Figure 1a
Figure 1b
While individual patients may claim benefit from a number of different foodstuffs, based on scientific
evidence, the only dietary components consistently shown to improve dry eye signs and symptoms are the
essential fatty acids.3, 4 Essential fatty acids are required by the body but cannot be synthesised therefore
they must be consumed either within dietary sources or in the form of nutraceuticals. The average
Western diet contains over twenty times more potentially detrimental Omega 6 than beneficial Omega 3.
Such Omega 6 fatty acids act as precursors for proinflammatory mediators, while Omega 3 fatty acids
function to inhibit the synthesis of these mediators. Good sources of Omega 3 fatty acids are cold fish
(e.g. mackeral, salmon and sardines), and flaxseed, walnut and canola oil. A carefully designed study,
conducted in the US, evaluated the diets of over 32,000 post-menopausal women and, controlling for
demographic factors, hormone therapy, and total fat intake, they found that a higher ratio of Omega 6 to
Omega 3 fatty acid consumption was associated with a significantly increased risk of self-reported dry eye
syndrome. Conversely, tuna consumption was inversely associated with dry eye syndrome such that those
eating between 5 and 6 servings of tuna per week were significantly less likely to report dry eye symptoms
than those eating 1 or fewer servings per week. The results were therefore able to suggest that a higher
dietary intake of Omega 3 fatty acids is associated with a decreased incidence of dry eye syndrome in
women, which is consistent with anecdotal clinical observations and proposed biological mechanisms.5
Periocular humidity increases can be achieved with the aid of moisture
chamber spectacles with side-shields. They may or may not include a
moist insert. This increased humidity has been shown to increase the
thickness of the lipid layer and lengthen the inter-blink interval.6
Although contact lenses are a recognised dry eye stimulus, in severe
dry eye, a bandage contact lens may be helpful in protecting and
hydrating the cornea. (Figure 2) Highly oxygen permeable materials
can enable overnight wear in some circumstances, and enhancements
in visual acuity and comfort, together with improvements in ocular
surface quality have been documented.7
Figure 2
Tear supplementation
Despite the range of management strategies for dry eye,
artificial tear supplements or lubricants remain the
mainstay treatment for dry eye. (Figure 3) A huge range
of products exists, varying in tonicity and in the
electrolytes, surfactants and viscosity agents that they
contain. Most products are isotonic, or are hypotonic in an
attempt
to
counteract
the
pro-inflammatory
hyperosmolarity of the dry eye tear film.8 Compatible
solutes such as glycerine and levocarnitine have recently
been incorporated in some products. They are believed to
play a role in osmoprotection, by forming a protective barrier between the hyperosmolar tears and the
epithelial cells at risk of damage. In terms of electrolytes, potassium and bicarbonate have been shown to
be most beneficial. Potassium has an important role in maintaining corneal thickness while bicarbonate
promotes wound-healing and helps to maintain normal epithelial ultrastructure. Based on its importance in
maintaining the protective mucin gel in the stomach, bicarbonate is also believed to benefit the gel-forming
ocular surface mucins.
Figure 3
Viscosity agents in artificial tear products increase retention time, and therefore effect, on the ocular
surface. For best patient compliance, viscosity should be matched as closely as possible to severity of
symptoms. Patients with mild-moderate dry eye are unlikely to tolerate the blurring of vision on instillation
and residue on eyelashes experienced with highly viscous solutions that the moderate to severe dry eye
patient will accept for the benefit of an increased period of comfort. Gels containing high molecular weight
carbomers offer superior retention times to most lubricant drops and are generally better tolerated than
petroleum-based ointments due to reduced blurring effects. Sodium hyaluronate (SH) is a naturally
occurring extracellular matrix glycosaminoglycan (GAG). As a tear supplement it has a number of useful
features. Its viscoelastic (non-Newtonian) rheological properties allow it to shear during eyelid movement
(i.e. during blinking), but to remain viscous between blinks, mimicking the natural tear film. The
mucoadhesive properties promote prolonged retention on the ocular surface and its excellent capacity to
bind and retain a significant quantity of water aids in corneal hydration. SH also has a vital role in cellular
development, in controlling inflammation, and in promoting wound-healing. CD44 is a cell surface adhesion
molecule for which SH is the ligand. Trauma and inflammation are associated with an increase in the
expression of CD44. Recent research has shown in in vitro studies of human epithelial cells, that the main
role of SH appears to be in promoting epithelial cell migration rather than either cell proliferation or
expression of CD44.9 The benefit of SH as a topical therapy is believed to lie in the adhesion between
CD44 on the cells and SH, which coats the exposed cornea, facilitating rapid epithelial cell migration and
subsequent wound closure. Of note to practising clinicians is that, in April 2008, the hyaluronic acid
category was approved for inclusion on the NHS Drug Tariff, enabling reimbursement.
SH has been shown to have beneficial effects in clinical trials. Johnson et al (2006) compared 0.1% and
0.3% SH to saline in moderate dry eye subjects and found that SH increased tear film stability and reduced
irritation symptoms in comparison to saline.10 In a more recent study, the same research group established
that, although drops containing 0.18% SH and 0.3% carbomer 934 were both effective therapies for
moderate dry eye, the SH-containing formulation was marginally more effective therapeutically, and also
less likely to cause blurring on instillation.11 Other researchers have evaluated SH in the treatment of
moderate dry eye with superficial keratitis. In a comparison of 1% carboxymethylcellulose (CMC) and
0.18% SH, again both treatments showed therapeutic benefit, but CD44 expression was decreased only
with the SH and subjects reported improved comfort levels with SH compared with CMC.12
Other formulations incorporate oil, in the form of castor or mineral oil, in
an attempt to supplement the tear film lipid layer.13, 14 Also directed
towards improving the lipid layer, is the recently developed liposomal
spray containing phospholipids in a stable form. The spray is applied to
the closed eye, and the liposomes spread onto the preocular tear film
surface, restoring the lipid layer. (Figure 4) In a recent randomised,
double-masked study, the liposomal spray was compared to saline.
Results of this study showed that the liposomal spray, applied to the
closed eye, significantly increased the thickness of the lipid layer and
significantly improved tear film stability, measured non-invasively, for up
to 90 minutes post-application. 15
Figure 4
Preservatives, particularly benzalkonium chloride (BAK) and the chelating agent EDTA, exacerbate ocular
inflammation associated with dry eye. Therefore non-preserved preparations are preferable, especially for
moderate-to-severe dry eye patients with increased levels of inflammation and repeated drop instillation.
Preference for the convenience and reduced cost of multi-dose preparations, however, has driven
manufacturers to develop products with less toxic preservatives, such as polyquad, sodium chlorite and
sodium perborate. The latter preservatives ‘disappear’ on instillation, converting to non-harmful byproducts, although care must be taken in severe dry eye patients in whom tear volumes are extremely low,
as total degradation of the preservative may not occur.1
Studies in the literature suggest that while most topical lubricants provide some relief, they do not entirely
resolve dry eye signs and symptoms. There is also little evidence to show that there is one product
significantly better than another. Most patients will state a preference for a particular product therefore it
may be necessary to try several products before achieving maximal patient satisfaction.
Retention of tears
Punctal Occlusion
While permanent punctal occlusion may be attempted surgically (canalicular ligature, canaliculectomy,
punctal tarsorraphy, ligature, and patching) or thermally (cautery, diathermy and argon laser), the majority
of punctal occlusion is temporary, using dissolvable or non-dissolvable punctal or intracanalicular plugs.
Short-term occlusion
Until recently, collagen plugs provided the practitioner with the ideal means of
conducting a trial of punctal plugs. These temporary plugs, made of bovine collagen,
are approximately 2mm in length and range from 0.2 to 0.6mm in diameter. (Figure 5)
Once inserted into the canaliculus, and in contact with the tear fluid, the plug swells
and blocks tear outflow. They are maximally effective over a period of approximately 3
– 5 days, dissolving completely within 7 – 10 days.
These collagen plugs composed of animal tissue, are still available for use in the US
and some other countries, but in early 2005, were withdrawn from the UK market due
to the unresolved concerns of the MHRA (Medicines and Healthcare Products
Regulatory Agency – An Executive Agency of the Department of Health, UK) over Bovine Spongiform
Encephalopathy (BSE). The resulting loss of CE mark on this product now prevents the distribution of all
brands of collagen plugs in participating EU countries, including the UK. Manufacturers state that work is
currently underway to develop a directly comparable synthetic replacement for collagen with a short
duration of action but no such products are available at the current time. Unfortunately, practitioners must
therefore rely upon the synthetic absorbable plugs as their temporary plug for trial purposes. The
disadvantage with regard to use for trial is the extended duration of effect of these
dissolvable plugs, which ranges between 2 and 6 months, as well as the increased cost.
Figure 5
Medium term occlusion
With their effect lasting for several months, synthetic absorbable intracanalicular plugs
have applications in post-LASIK dry eye, which, for the majority of affected individuals, is
a temporary phenomenon. The plugs are available in a range of diameters. (Figure 6)
Long term occlusion
Non absorbable punctal or intracanalicular plugs are
designed to remain in place indefinitely, although they can be
Figure 6
removed (with variable degrees of success) if deemed necessary.
Most silicone punctal plugs are based on the design of Freeman, with a
flange that sits exterior to the punctum, a narrower neck sitting within the
punctal opening and a wider base that serves to occlude the canaliculus.16
(Figure 7) The flange allows the clinician to confirm that the plug is in place
Figure 7
and enables straightforward removal if the need arises. A sizing gauge must
be used to select the most appropriate size of punctal plug, as too large a
plug risks extrusion and too narrow a plug risks insertion below the punctal
ring. (Figure 8) Some patients are aware of mild irritation from the flange of
these plugs when in place, and may prefer an intracanalicular style of plug.
Silicone intracanalicular plugs (Herrick plugs, Lacrimedics Inc.) resemble golf
tees in appearance, and on insertion sit at the narrowed portion of the
canaliculus. (Figure 9) Removal, if necessary, is by irrigation only, but this is
difficult to confirm and it has been reported that such plugs can become
lodged and infected within the lacrimal sac,
Figure 8
necessitating complex nasolacrimal duct surgery for removal.17 More
recently developed materials for long-term occlusion include a hydrogel
polymer (Form Fit , Oasis Medical Inc., CA, USA), which is inserted as a
rigid rod into the canaliculus where it rapidly absorbs fluid and takes up the
shape of the canaliculus, occluding tear flow. Similarly, the SmartPlug
(Medennium Inc., CA, USA) is supplied as a long narrow rod, for insertion
into the canaliculus. This thermodynamic hydrophilic acrylic material then
Figure 9
shortens in length and increases in diameter at body temperature, occluding
the canaliculus.18
Improvement in dry eye symptoms has been documented in up to 86% of patients fitted with punctal plugs.
Signs of dry eye have also been reduced, including improved tear film stability, reduced corneal staining
and decreased osmolarity. The risk of infection with properly fitted punctal plugs is small, but patients
should be aware of relevant signs, and understand the importance of seeking advice should redness or
pain occur. Before fitting, fully informed consent should be obtained for this relatively invasive procedure.
Care must be taken to select patients appropriately. Lid disease is a contraindication to punctal plugging,
significantly increasing the risk of infection, therefore any concurrent blepharitis, for example, must be well
controlled prior to considering this treatment modality. Punctal plugging is indicated for patients with a
demonstrable aqueous deficiency. Those with poor tear quality leading to an evaporative dry eye, rather
than a reduced quantity of tears, seldom experience relief with punctal plugging, and may even suffer
epiphora.
Tear stimulation
Topically applied secretagogues, including diquafosol (which stimulates both aqueous and mucin
secretion) and 15-S-HETE (a mucin stimulant) are currently under investigation by pharmaceutical
companies, and may provide benefit to dry eye patients in the future. Currently available in the US, the
systemically administered cholinergic agonists, pilocarpine and cevimeline, have been shown to improve
signs and symptoms of dry eye, but the drug-induced side effects, particularly of pilocarpine, limit the
popularity of these agents.19
Anti-inflammatory Therapy
Inflammation is recognised to be a key component in the pathogenesis of dry eye. Anti-inflammatory
treatments thus have enormous potential in the management of ocular surface disease.
Corticosteroids
Corticosteroids are potent anti-inflammatory agents, which directly regulate gene expression through
traditional glucocorticoid receptor-mediated pathways, and interfere with transcriptional regulation of proinflammatory genes through non-receptor pathways. They have the ability to inhibit inflammatory cytokine
and chemokine production, decrease synthesis of MMPs and cell adhesion molecules, and stimulate
lymphocyte apoptosis. Clinical studies have reported improvement in dry eye signs and symptoms
following corticosteroid therapy, without steroid-related complications, at least in the short-term.20 However,
the significant risk of toxicity in the longer term, limits the usefulness of corticosteroids for the treatment of
chronic dry eye.
Cyclosporin
The fungal-derived peptide, cyclosporin A (CsA), is a potent immumodulatory agent, which inhibits T-cell
activation and inflammatory cytokine production, through interference with cytoplasmic transcription, and
also inhibits apoptosis. Clinically, CsA has been shown to reduce conjunctival rose Bengal staining and
superficial punctate keratitis and to improve symptoms in moderate-severe keratoconjunctivitis sicca.21
Combined, the results of two independent Phase III clinical trials showed that, relative to the vehicle, 0.05%
or 0.1% CsA significantly improved corneal fluorescein staining and the Schirmer test score with
anaesthesia, both regarded as objective signs of dry eye disease. In the patients treated with CsA, 59%
demonstrated increased Schirmer wetting with 15% exhibiting an increase of 10mm or more. In
comparison, only 4% of the subjects treated with the vehicle showed this magnitude of improvement.
However, while there appears to be a valuable role for CsA in the more severe forms of aqueous-deficient
dry eye, the role in mild-moderate dry eye is less convincing. The commercial product, Restasis (Allergan
Inc), was FDA approved in 2002.
Natural tear substitutes
The healthy tear film contains a number of components, which are critical in the maintenance of corneal
and conjunctival integrity but, have yet to be successfully replicated or incorporated in a stable form, in
synthetic ophthalmic products. Autologous serum, the product of whole blood that remains after clotting,
contains components such as epidermal growth factor (EGF), vitamin A, transforming growth factor(TGF- ), fibronectin, substance P, insulin-like growth factor 1 (IGF-1), nerve growth factor (NGF), and other
cytokines necessary for the proliferation, differentiation, and maturation of the normal ocular surface
epithelium.22 Autologous serum eye drops have been shown in a number of studies to successfully treat
severe dry eye across a range of ocular surface disorders. These include Sjögren’s syndrome, graftversus-host disease (GVHD), superior limbic keratitis, Stevens-Johnson syndrome, cicatricial pemphigoid,
LASIK, neurotrophic keratopathy and persistent epithelial defects.
The production of autologous serum eye drops is labour-intensive and strict protocols must be followed in
the selection of patients and in the preparation and storage of the drops.23 As a result, serum eye drops
can be a relatively expensive option, with the cost per day being equated to that of a bottle of preserved
lubricant.24 However, recent research, suggests that for those patients unable to obtain relief from maximal
lubricant therapy and/or punctal plugging, autologous serum treatment is a management option worthy of
consideration.
In individuals with end stage dry eye disease and no aqueous tear production, salivary submandibular
gland transplantation may be considered. Following the combined maxillofacial and ophthalmic surgery,
patients might expect comfort to be improved, and dependence on tear supplements to be reduced, but
often no improvement in vision is observed.25
Tetracyclines
Oral tetracyclines and their derivatives (e.g. doxycycline) are recognised both for their antimicrobial and
anti-inflammatory properties. Decreased levels of toxic meibomian gland breakdown products are the result
of the antimicrobial activity, which is believed to take effect through inhibition of staphylococcal lipase and
lipolytic exoenzyme production.26 Administered in lower concentrations, the anti-inflammatory properties of
the tetracyclines make them suitable for treatment of chronic inflammatory eyelid disease (meibomianitis),
particularly that associated with ocular rosacea. Tetracyclines decrease the production of interleukin-1 (IL1) and tumour necrosis factor- (TNF- ), and decrease the activity of collagenase, phospholipase A2 and a
number of matrix metalloproteinases.
Eyelid therapy
Lid hygiene
The use of lid scrubs is recommended for patients with blepharitis (seborrhoeic or staphyloccal) to reduce
the inflammatory load. A number of sterile, single-use, lid scrub products are available. Also available is a
hypoallergenic foaming lid cleanser (TheraTears SteriLid, Advanced Vision Research, MA, USA), which
also contains tea-tree oil, to help control Demodex infestation.27 If a significant Demodex infestation is
identified by cylindrical collarettes around the eyelash bases, a once weekly lid scrub using a 50% solution
of tea-tree oil is recommended in addition to this daily lid clean. Patients must be reminded that lid hygiene
is an ongoing therapy, which must be performed regularly, in order to maintain reduced symptoms. Once
control is achieved in mild cases, it may be possible to reduce the frequency of treatment, but not cease
treatment altogether.
Warm compresses
Warming the meibomian secretions facilitates outflow in patients with meibomian gland dysfunction. Warm
compresses can be fashioned in a number of ways, from a hot, damp washcloth to a warmed, muslincovered river stone. An alternative is the commercially-produced MGDRx EyeBag (EyeBag Company,
Halifax, UK). (Figure 10(a)) This is a pouch filled with flaxseeds which is heated in the microwave for 30
seconds and placed over the closed eyes for 5 minutes, prior to gentle eyelid massage to encourage flow
of the meibomian oils onto the surface of the tear film. (Figure 10(b)) The use of warm compresses has
demonstrated significant improvements
in tear film stability and lipid layer
thickness and a decrease in tear film
Other heat
evaporation rate.28
treatments include latent heat goggles,
29
and a warm moist air device,30 both of
which have been shown to improve tear
film characteristics in dry eye patients.
Figure 10a
Figure 10b
Topical antibiotics
A mild topical antibiotic, such as fusidic acid 1% (Fucithalmic), may be indicated to help decrease
staphylococcal infection. It will not eradicate bacterial infection, and while it may help to break the cycle of
inflammation and reduce symptoms, it is a short-term solution and not a substitute for good eyelid hygiene.
Tailor the therapy to the dry eye aetiology wherever possible:
Lid disease / lipid
Aqueous deficiency Mucin deficiency
deficiency
Blinking exercises
Tear supplements /
Mucomimetic drops /
hyaluronic acid
HP Guar
Lid hygiene / warm
Punctal occlusion
Secretagogues
compresses
Tea tree oil
Cyclosporin A (US)
Mucomimetic gels /
(Demodex)
ointments
Topical antibiotics
Secretagogues
Lipid drops / sprays
Moisture retaining
goggles/spectacles
Tetracyclines
Ocular surface
inflammation
Autologous serum
Corticosteroids
Tetracyclines (eyelid)
Cyclosporin A (US)
Table 2: Suggested treatments for specific tear film or ocular surface deficiencies or inflammation
There have been significant advances in the treatment and management of dry eye in recent years. A
number of management strategies exist and these should be considered either alone, or in combination, as
indicated from the results of careful tear film and ocular surface testing. As the pathophysiology of dry eye
has become better understood, treatments are evolving from substances that simply hydrate the ocular
surface to therapies that inhibit inflammation, stimulate natural production of tear constituents, and
maintain ocular surface health and function. It is anticipated that as new therapies become available and
are introduced to clinical practice, the quality of life for individuals affected by dry eye disease will continue
to be improved.
Figure Legends
Figure 1:
Exposed ocular surface area can be reduced significantly, (b) compared with (a), by
lowering computer monitor height.
Figure 2:
Bandage contact lenses may provide relief for some dry eye patients
Figure 3:
A typical range of artificial tear products on the Pharmacy shelf
Figure 4:
Liposomal spray, designed to enhance the tear film lipid layer, applied to the closed eye
Figure 5:
Collagen plugs, providing up to a week of intracanalicular occlusion, can no longer be used
in the UK
Figure 6:
Synthetic absorbable intracanalicular plug (blue) immediately prior to insertion into the lower
punctum. Occlusion with these plugs typically lasts between 2 and 6 months
Figure 7:
Silicone (Freeman style) punctal plugs provide permanent (although reversible) occlusion
Figure 8:
Gauging tool used to estimate the size of the punctum, prior to selection of the appropriate
punctal plug
Figure 9:
Herrick plug (Lacrimedics Inc., USA) for intracanalicular occlusion
Figure 10:
Treatment for meibomian gland dysfunction. The warm compress (MGDRx EyeBag) is
placed over the eyelids for several minutes (a) prior to gentle digital manipulation to
enhance expression of meibomian fluid (b)
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