Ординатура / Офтальмология / Английские материалы / Ocular Therapeutics Eye on New Discoveries_Yorio, Clark, Wax_2007

manage other immunological failings such as autoimmunity and allergy.

II. IMMUNE-MEDIATED OCULAR

DISEASES

A. Allergy

1. Clinical disease

The term atopy is used to indicate allergic disorders and the predisposition for conditions such as seasonal rhinitis, perennial rhinitis, asthma, atopic dermatitis, food allergies, urticaria, and non-hereditary angioedema (Bloch, 1968). Ocular allergy is estimated to affect 20% of the population on an annual basis, and the incidence of allergic eye disease is known to be increasing (Abelson and Schaefer, 1993). Approximately one-half of patients with ocular allergy have a personal or family history of atopy (Doshnik and Ehlers, 1994).

The importance of ocular allergy is due more to its frequency than to its severity and capacity to cause lossof vision. However, two relatively uncommon types of allergic eye disease, atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC), if not treated properly, can cause severe damage to the ocular surface, leading to corneal scarring and vision loss. With ocular allergy, itching, tearing, redness, burning, photophobia, and mucus discharge can occur. Common forms of ocular allergy include acute allergic conjunctivitis, seasonal allergic conjunctivitis (SAC), and perennial allergic conjunctivitis (PAC). Allergic conjunctivitis has an average age of onset of 20 years of age, and is principally a disease of young adults. Symptoms tend to decrease with age. Each of the forms of allergic conjunctivitis is associated with specific clinical features.

Acute allergic conjunctivitis is an acute a hypersensitivity reaction caused by environmental exposure to allergens. It is characterized by intense episodes of itching, hyperemia, tearing, chemosis, and eyelid

edema. It typically resolves in less than 24 hours, regardless of treatment. SAC goes by several other names, including allergic conjunctivitis, hay-fever type conjunctivitis, or allergic rhinoconjunctivitis. It is a mild form of ocular allergy, and it is frequently associated with rhinitis. It occurs in the spring and late summer, and is caused by exposure in sensitized individuals to pollen, grasses, and ragweed. PAC is a mild, chronic, allergic conjunctivitis related to environmental exposure to year-round allergens such as dust mites and mold.

Less common forms of ocular allergy include VKC, which is a rare, sometimes severe, bilateral, chronic disease that primarily affects young boys. Age of onset is typically quite young, approximately the age of seven. It affects males to females at a ratio of 3:1. Patients typically “outgrow” the disease with the onset of puberty. Exacerbations are common in the spring (hence the name “vernal”), and it occurs mainly in warm, dry climates. Giant papillae on the upper tarsus, thick mucus discharge, and corneal ulcers are characteristic. VKC is rare in Northern Europe and the temperate areas of North America. It is more common in climates such as the Mediterranean, Central America, and South America.

Perhaps the most severe form of ocular allergy, and the one type most associated with vision loss, is AKC. The term is a little misleading, as the other conditions are also atopic in nature. Still, the term AKC is used primarily to refer to a relatively uncommon form of severe, bilateral, chronic disease. It primarily affects adults, typically over the age of 40, and is slightly more common in men than women (Hanifin, 1987). AKC is characterized by thickened, eczematous eyelids and severe itching. Frequently, it is associated with blepharitis, and it can sometimes be associated with cataracts, keratoconus, and rarely retinal detachment. Since AKC is characterized by chronic inflammation of the lid margins and surface epithelium of the conjunctiva and cornea, destruction of the underlying conjunctival and corneal

stromal matrix can be significant with time. In addition to corneal scarring, these patients may develop punctual obliteration, forniceal foreshortening and symblepharon formation, severe lid margin disease including meibomian gland dysfunction (with resultant evaporative dry eye), cicatrizing entropion and poor lacrimal pump function (occasionally with associated epiphora). These eyes can therefore be intermittently dry or moist, based on whether the pathology primarily affects the meibomian gland or pump function.

Environmental exposure is a critical factor in determining allergic disease severity. Seasonal allergens include pollens in the spring, grasses in the summer, and ragweed in the late summer and early fall. Perennial allergens include house dust mites, molds, and animal dander. Acute allergic conjunctivitis can occur with any of these allergens, but the reaction is usually of less than 24 hours in duration. Hence, whether the condition manifests itself as acute, seasonal, or perennial depends upon the types of allergen, the exposure to and volume of allergen, the duration of exposure, and the individual’s response to the causative agent. Acute allergic conjunctivitis occurs rapidly upon exposure to what is usually a known allergen, such as cat dander. Symptoms can be severe and debilitating but resolve quickly, usually within 24 hours of removal of the allergen. By comparison, SAC typically has a less dramatic onset; it will have a more predictable and chronic course that corresponds to the ragweed (late summer and early fall), grass (summer), and pollen (spring) seasons.

2. Basic mechanisms

In all forms of ocular allergies, the clinical manifestations are directly or indirectly attributable to mast cell activation and degranulation. Conjunctival mast cells occur in two forms based on the expression of two proteases, tryptase and chymase. Mast cells (MC) found in the skin contain both tryptase

and chymase, while MC in mucosal tissues, such as the conjunctiva, contain only tryptase (Irani et al., 1990). Allergic responses at the ocular surface are initiated when conjunctival mast cells are stimulated through the high affinity receptors for IgE antibodies (FcεR1).This usually occurs when a multivalent allergen cross-links IgE antibodies that are specific for the allergen and are bound via their Fc moiety to the FcεR1 on the surface of the MC. This results in the release of histamine and a variety of mediators including: prostaglandin D2, leukotrienes, tryptase, carboxypeptidase- A, cathepsin-G, platelet activating factor (PAF), eosinophil chemotactic factor (ECF), and other granulocyte chemoattractants (Anderson, 2001). In addition, MC also produce and release a variety of cytokines including IL-4, IL-5, IL-6, IL-8, IL-13, and TNF-α (Bradding et al., 1992; Macleod et al., 1997; Zhang et al., 1998). The MC-derived mediators and chemokines affect multiple organs and cells resulting in complex vasoactive changes and an inflammatory cascade. The pathological sequelae include vasodilatation, increased conjunctival vascular permeability, inflammatory cell infiltration, itching, chemosis, and edema.

Ocular surface allergy develops in two phases, an early phase reaction (EPR) and a late phase reaction (LPR). The EPR occurs within minutes after exposure to the allergen, lasts for up to 20 minutes and is characterized by erythema and edema that are the result of increased vascular permeability produced by vasoactive amines, such as histamine, that are released by MC in conjunctival mucosa. The LPR develops 2–12 hours after initial exposure to the allergen and is the product of cellular infiltration in response to chemokines (e.g. ECF) and cytokines released by the degranulating mucosal MC. The cellular infiltrate includes eosinophils, neutrophils, and lymphocytes.

The pathophysiology of allergic conjunctivitis involves more than immediate hypersensitivity responses. T-cell-mediated inflammation has been implicated and

there is evidence from animal studies that the Th1 cytokine, interferon-γ (IFN-γ), is needed for the full expression of allergic conjunctivitis (Stern et al., 2005a). Although IFN-γ is known to cross-regulate Th2 cells and down regulate the expression of Th2 cytokines, it is nonetheless a pleiotropic cytokine that also influences the behavior of various inflammatory cells and the expression of numerous cell surface molecules. One intriguing possibility is that IFN-γ exacerbates the inflammatory phase of allergic diseases by upregulating cell adhesion molecules, such as vascular endothelial cell adhesion molecule-one (VCAM-1) (Stern et al., 2005a). VCAM-1 expression is greatly diminished in the conjunctival blood vessels in IFN-γ knockout mice and in wild-type mice treated with anti- IFN-γ antibody (Stern et al., 2005a). Interestingly, the diminished VCAM-1 expression in these mice is associated with a steep reduction in the expression of allergic conjunctivitis and reduced inflammatory infiltrates into the affected conjunctiva (Stern et al., 2005a). Thus, IFN-γ could act at the end stage of allergic conjunctivitis by acting as a “gatekeeper” to regulate the trafficking of inflammatory cells into the conjunctiva (Stern et al., 2005a,b).

Tissue remodeling is a feature of many allergic diseases, including chronic allergic conjunctivitis. Increased expression of collagen and fibrosis is found in patients with VKC. Interestingly, one study has reported the upregulation of TNF-α, TGF-β, basic fibroblast growth factor, and plateletderived growth factor in VKC tissue biopsies (Leonardi et al., 2000). The overproduction of collagen types I and VI reported in this study is consistent with the idea that fibrosis is a byproduct of chronic allergic inflammation in the conjunctiva.

Basophil degranulation is also activated by IgE-mediated mechanisms. In addition, basophils are activated by an array of other chemical mediators, and basophils have been found to be elevated in tears 6 hours after allergen challenge. Thus, these cells may play a role in the late phase reaction,

which follows the immediate allergic response in the conjunctiva. Eosinophil migration occurs 1 to 6 hours after antigenic challenge. They release a range of preformed and newly synthesized mediators. Eosinophils are known to be increased in the conjunctiva and tears in patients with SAK, VKC, and GPC. Neutrophils are attracted to the conjunctiva by chemotactic factors (e.g. chemokines) approximately 6 hours after conjunctival challenge.

B. Current and Future Therapy

1. General management guidelines

Regardless of the specific clinical allergic syndrome, avoidance of the allergen is the primary therapy whenever possible. Preventive steps include limiting outdoor exposure during high “counts” of pollen and ragweed, use of air conditioning, keeping car and home windows closed during the peak seasons, and covering the eyes with glasses to reduce allergen landing on the eye surface. Other preventive measures may include replacement of old pillows and mattresses, effective covers for pillows and mattresses, frequent washing of bedding, reducing humidity, and frequent vacuuming and dusting of the house. Additionally, other reservoirs of dust should be removed such as old carpets, old furniture, and old curtains or drapes. When the allergen is animal dander, the animal may need to be removed from the house, and old carpets, furniture, and curtains should be removed or cleaned frequently. In all types of allergic conjunctivitis, patients should not rub their eyes because this can cause mechanical mast cell degranulation and worsening of symptoms. Instead, during acute episodes of itching, patients should be instructed to use topical antihistamines, frequent artificial tears, and cool compresses.

2. Specific therapeutic agents

a. Mast cell stabilizers – The primary goal of pharmacological therapy in allergic eye

disease is prevention of mast cell degranulation. Many different mast cell stabilizers exist currently in the market. Cromolyn sodium (Crolom) was one of the earliest to be developed; many others followed including lodoxamide (Alomide). These drugs are particularly useful for seasonal and perennial allergic conjunctivitis. Since the onset of action is 5 to 14 days after therapy has been initiated, these medicines are less useful for acute conjunctivitis. In addition to preventing mast cell degranulation, mast cell stabilizers may inhibit leukocyte activity. They may also dampen mediator release from mast cells, basophils, eosinophils, and neutrophils (Berdy et al., 1989).

b. Antihistamines – Antihistamines competitively and reversibly block histamine receptors in the conjunctiva and eyelids (Abelson and Weston, 1987). Thus, the action of the mast cell’s main mediator is blocked. The full effect of oral administration of antihistamines occurs hours to days after initiating therapy, and consequently these drugs are best utilized prophylactically. In addition, since oral antihistamine use is associated with drying of mucosal membranes, the use of oral antihistamines may worsen allergic symptoms. This effect is not thought to be significant with topical antihistamine use.

There are many topical antihistamines currently available. The advantages of topical antihistamine usage include a more rapid onset of action, direct application to the conjunctiva, and reduced systemic side effects such as drowsiness and dry eyes (Stokes and Feinberg, 1993). They have also been noted to decrease vascular permeability and vasodilatation (Bahmer and Ruprecht, 1994). The use of topical antihistamine/vasoconstrictor combinations have been shown to be more effective than either one used alone. In a report describing two studies of 25 subjects each, the combination of an antihistamine and a vasoconstrictor produced significantly better whitening and inhibition of itching compared to either agent alone in a hista- mine-induced red itchy eye model (Abelson

et al., 1980). In addition to the antihistamine actions, the vasoconstrictors activate the post-junctional, alpha-adrenergic receptors found in blood vessels, and they cause vasoconstriction and decreased conjunctival edema.

Olopatadine (Patanol) is the first drug to receive approval as a combination antihistamine and mast cell stabilizer. It has become the most commonly prescribed drug among many physicians when treating various types of ocular allergy. The H1-receptor selectivity is superior to that of other antihistamines (Sharif et al., 1996). Patanol is considered very safe and effective. Common side effects include stinging upon instillation, and headache. It is approved for children older than 5 years of age and adults. There is a new class of triple-action drugs; they are a combination of H1-receptor antagonists, mast cell stabilizers, and NSAIDs. They include Optivar (azelastine HCl), Alocril (nedocromil), Alamast (pemirolast potassium), and Zaditor (ketotifen fumarate). Dosing is twice per day.

c.Non-steroidal anti-inflammatory drugs –

NSAIDs block the action of cyclooxygenase and thus inhibit the conversion of arachidonic acid to prostaglandins and thromboxanes. While they have been promoted as treatments for ocular allergy, among other indications for which they are highly effective (such as prophylaxis against intraoperative miosis, and post-operative cystoid macular edema, to name a few), NSAIDs are not considered to be as effective as other medical therapy in treating allergic ocular disease. Topical NSAIDs use may also be associated with corneal melting in patients who are predisposed to melts, specifically those patients with pre-existing collagenvascular disease and in patients with preexisting ocular surface disease, such as severe dryness.

d.Corticosteroids –Corticosteroidssuppress the late phase reaction in both experimental

and clinical settings (Schleimer, 1990). Corticosteroids in part inhibit the inflammatory cascade by inhibiting phospholipase A2, and consequently, they reduce the formation of lipid-derived mediators from arachidonic acid. This prevents leukocyte migration, hydrolytic enzyme release, fibroblast growth, and changes in vascular permeability. However, since they are associated with serious side effects (cataracts, elevated intraocular pressure, glaucoma, and secondary infections), they should only be used for short “pulse therapy” among patients in whom antihistamines and mast cell stabilizers provide inadequate therapy. Among all topical steroids, prednisolone acetate 1% has the greatest risk of raising IOP, with Dexamethasone phosphate 0.1% having the next greatest risk. By comparison, “soft” steroids are a group of topical corticosteroids that have a greatly reduced risk of causing increased IOP, since they are formulated such that they undergo rapid inactivation upon penetration of the cornea (Druzgala et al., 1991). These drugs include Pred Mild (prednisolone), FML (fluoromethalone), Lotemax (loteprednol), and Vexol (rimexolone).

e. Cyclosporine – Cyclosporine A is known to inhibit the effect of interleukin-2 on T-lymphocytes. It inhibits the clonal expansion of helper T-cells. It may also inhibit mast cell proliferation and survival. Topical cyclosporine 2% (a dose considerably higher than the 0.05% topical formulation (Restasis) marketed for treatment of dry eyes) has been shown to be effective in treating VKC; however, relapses can be observed after therapy is discontinued. Systemic cyclosporine can be helpful in controlling severe cases of allergic ocular disease and thereby reduce the need for long-term corticosteroid use. However, no controlled study has been performed evaluating the utility of systemic cyclosporine in the treatment of ocular allergy. The patient must be closely monitored for any adverse effect upon kidney function, bone marrow suppression,

hypertension, tremor, hirsutism, and gingival hyperplasia, among other side effects.

3. Future therapies

It is expected that we will see many new treatments in the management of ocular allergy in the coming years. First, it should be recalled that activation and mobilization of APCs is an early mechanism that precedes lymphocyte activation, and the resultant production of IgE that binds mast cell membranes. Hence, strategies that suppress APC recruitment, such as local blockade of interleukin-1, may prove useful in suppressing allergic responses, as has been shown in a mouse model of ocular allergy (Keane-Myers et al., 1999). Second, there is increasing interest in novel methods of preventing histamine action, including novel histamine blockers that can bind not only the H1 receptor, but potentially other histamine receptors. Novel histamine receptor blockers or histamine-binding molecules may be developed with potential future applications to ocular allergy. Third, as discussed above, vascular leakage is an important aspect of the pathophysiology of allergic tissue damage. Hence, targeting cell adhesion factors (such as VCAM-1, ICAM-1, and integrins) or factors that mediate leakage (e.g. vascular endothelial growth factors (VEGF)) may prove to be effective in suppressing the expression of atopy in tissues including the conjunctiva. Fourth, there has been considerable interest in the development of strategies that block the effect of chemokines in allergy. Chemokines are small molecular weight cytokines that direct leukocyte trafficking in tissues. Specific chemokines have been identified that selectively bind receptors (e.g. CCR3) on mast cells and eosinophils, for example, which amplify recruitment of these critical cellular effectors in allergy. Significant effort is under way to develop novel strategies for antagonizing these ligand-receptor systems in a variety of atopic conditions, including ocular allergy. Finally, as discussed

in detail above in the section “Basic principles of regional immunity in the eye and ocular immune privilege”, immunity is not limited to generation and expression of responses that are pathological to tissues. Induction of tolerance is an active mechanism by which the immune system tempers its response to self and foreign antigens in a manner compatible to health. Similarly, generation of tolerance to potentially allergic substances has been shown to carry considerable merit in attenuating the Th2 response in several different forms of allergy, including allergic airway disease. Proof of how tolerance can be effectively generated to substances on the ocular surface awaits further research, but is certainly conceivable in the not-too-distant future.

C. Dry Eye Syndromes

1. Clinical disease

There are numerous definitions in current use for dry eye syndromes (DES) and keratoconjunctivitis sicca (KCS), terms that are often used interchangeably. The most widely acknowledged definition remains that developed nearly a decade ago by the National Eye Institute/Industry Workshop on Dry Eye, which defines DES as a group of conditions affecting the ocular surface and tear film characterized by reduced tear production and/or excessive tear evaporation associated with symptoms of ocular discomfort (Haas, 1964). Several aspects of this definition warrant special comment. First, DES refers to a heterogeneous group of conditions that share dryness and surface epithelial disease as common characteristics. Second, the inclusion of symptoms in the definition of dry eye is of critical import – namely, the diagnosis of ocular surface epithelial disease/staining alone cannot signify DES unless the patient also complains of symptoms compatible with dry eye.

Common risk factors for DES include advanced age, female gender, postmenopausal status, smoking, autoimmune

disorders, contact lens wear, anti-choliner- gic medications, eyelid disorders, and other anatomical causes of increased exposure of the ocular surface. An exhaustive review of the protean clinical manifestations of DES and its etiologies is well beyond the scope of this chapter. We shall therefore limit this discussion to a review of broad areas in the pathogenesis and treatment of DES, with particular emphasis on matters related to inflammation and immunity.

The tear film is a complex fluid mixture. The aqueous portion is secreted by the main and accessory lacrimal glands; the lipids by the meibomian glands in the eyelids; the mucins by the goblet cells of the conjunctiva and the corneal and conjunctival surface epithelia. The mucins are products of the surface epithelia, in particular the goblet cells of the conjunctiva that secrete copious amounts of gel-forming mucins that cover the epithelium and mix with the overlying aqueous phase. These mucins play a critical role in decreasing surface tension on the ocular surface, thereby allowing for the even spreading of the tears. Additionally, many proteins, including immunoglobulins and defensins, mix with mucins, and hence the mucins play a critical role in host defense against pathogens by providing a physical barrier against penetration of pathogens across the surface epithelium. Secretion of tears (the aqueous and its many contents, including a vast array of immunoglobulins, lymphocytes, and proteins, including cytokines critical for defense against pathogens and healthy maintenance of the surface epithelium) is under neuronal and hormonal (primarily androgens) regulation. Disruption of the hypothalamic/pituitary/ gonadal axis results in atrophy of the lacrimal gland, a decrease in fluid and protein secretion and apoptotic cellular changes. Neuro-hormonal regulation of lacrimal gland secretion in turn is affected and in part controlled by the immune system. The lacrimal gland includes many CD4 and CD8 lymphocytes, dendritic cells, macrophages, and mast cells; in humans, plasma

cells account for more than 50% of all the mononuclear cells in lacrimal tissue (Wieczorek et al., 1988). As an example of how neuro-hormonal factors interact with the immune system, the secretion of secretory IgA (sIgA), the predominant immunoglobulin in tears, is under the control of androgenic steroids.

The most superficial layer of the tear film is produced by the meibomian glands in the tarsal plate, which secrete sebaceous material at the mucocutaneous junction of the lid margin. This layer has a major role in retarding evaporation of the tear film. Many factors, including possibly the diet, can lead to alterations in the composition of the meibum secreted by the meibomian glands. However, the most common underlying cause of evaporative tear insufficiency is posterior lid margin disease due to chronic inflammation, as seen in chronic non-infectious blepharitis, a common finding in rosacea.

2. Basic mechanisms

While the cornea is the most critical tissue affected in DES, and the one whose involvement is most closely associated with symptoms and diminished vision, it is the conjunctiva that is typically affected first. Initially, there is loss of conjunctival goblet cells (Abdel-Khalek et al., 1978) and edema of the conjunctival stroma (Gilbard et al., 1987). This is followed by intercellular edema in the deeper layers of the conjunctival epithelium and then by intracellular edema as the disease progresses. Squamous metaplasia of the conjunctiva occurs with further decrease in conjunctival goblet cell density. Recently, it was shown that patients with moderate dry eye had higher conjunctival HLA-DR-positive cells compared with controls, with HLA-DR expression pattern in mild and moderate dry eyes reflecting disease progression (Rolando et al., 2005).

The etiology of dry eye disease is clearly multifactorial, and it is rare that DES can be

associated with any one single factor. This is so because the ocular surface, the tearsecreting glands, the neural innervations, and the neuroendocrine factors function as an integrated “unit”. When dysfunctional, this unit results in an unstable tear film causing ocular surface disease. Age, decrease in supportive factors (androgen hormones), systemic inflammatory disease (rheumatoid arthritis), ocular surface diseases (HZV), trigeminal nerve severing (LASIK), and efferent cholinergic nerve disruption (anticholinergic drugs) are all potential proximate causes of the dysfunction of this integrated functional unit. Regardless of cause, however, it now appears that T-cell-mediated inflammation plays a critical part in mediating the pathology observed in dry eye syndrome (Kunert et al., 2000; Solomon et al., 2001). Overexpression of pro-inflammatory cytokines, such as interleukin (IL)-1, 6, 8, and interferon (IFN)-gamma, has been observed in both the ocular surface and tear film of clinical and experimental (animal models of) dry eye (Pflugfelder et al., 2000). Additionally, enhanced expression of cell adhesion factors (e.g. ICAM-1) and chemokines/ chemokine receptors (e.g. CCR5) (Gulati et al., 2006), leads to recruitment of bone marrow-derived leukocytes and T-cells that can in turn cause apoptosis of the surface epithelium. The abnormal ocular surface fails to wet properly, and a vicious cycle of inflammation is amplified involving both soluble and cellular mediators (Hamrah et al., 2004).

These strong correlations between ocular surface inflammation on the one hand, and DES on the other hand, notwithstanding, there continues to be much debate as to whether the role of immunity is correlative (e.g. in amplifying the disease process) or causal. Recent evidence from experimental dry eye in mice strongly suggests that T- cells (in particular the Th1 cells of the CD4 compartment) play a critical part in inducing, at least some forms of, DES. Niederkorn and colleagues have shown that desiccating stress leads to induction of CD4 cells that,

when adoptively transferred to other mice (including those not exposed to desiccating stress), can induce T-cell infiltration of the cornea, conjunctiva, and lacrimal gland (Niederkorn et al., 2006b). In addition to directly implicating T-cells in the pathogenesis of the condition, these observations suggest that exposure to a dry environment leads to induction of an adaptive T-cell response to a shared epitope in these critical tissues that can induce and sustain pathology. The precise contribution of T-cells to DES pathogenesis in the clinical setting remains an area of intense investigation. As stated above, however, the etiopathogenesis of a complex chronic condition such as DES appears to be due to multiple factors/ mechanisms. Below, we will briefly summarize some factors associated with the two most common subtypes of DES-lacrimal insufficiency and meibomian gland disease.

a. Lacrimal gland disease – The most significant anatomic cause of lacrimal gland dysfunction is damage from an (auto) immune mechanism, such as seen in Sjogren’s syndrome (SS). Lacrimal gland tissue from SS patients shows mononuclear cell infiltration with lymphocytes, both CD4 Th1 cells and IgG-producing B cells, some follicle formation, plasma cells, and atrophy of secretory epithelial tissue with deposition of collagen (Bloch et al., 1965; Font et al., 1967). This is analogous to changes occurring in the salivary glands which can cause dry mouth (xerostomia). One of the most immediate effects of decreased lacrimation on the ocular surface is tear hyperosmolarity. The hyperosmolarity in KCS is thought to be from increased electrolytes, particularly sodium; and this change can lead to a cascade of changes that can be pathological to the ocular surface. For example, hyperosmolar saline has been shown both in vivo and in vitro (on cultured corneal epithelial cells) to activate inflammatory pathways, including stressactivated protein kinases such as p38, involved in the mitogen-activated protein kinase (MAPK) signaling pathway, c-jun

NH(2) terminal kinase (JNK), matrix metalloproteinases, and inflammatory cytokines such as IL-1 and TNF-alpha, thereby relating hyperosmolarity to the molecular pathways that can mediate ocular surface inflammation and epitheliopathy (Li et al., 2004; Luo et al., 2005).

b. Meibomian gland dysfunction (MGD) – In patients with MGD (e.g. in association with facial rosacea) there is progressive stenosis or closure of the meibomian gland orifices which leads to alterations in the level of secretion and/or lipid profile of the oils that cover the aqueous phase of the tear film, with the end result being a hyperevaporative state associated with DES. This enhanced tear film evaporation results in an increase in tear film osmolarity, which itself contributes to ocular surface disease as described above. MGD frequently accompanies aqueous insufficiency; indeed, many SS patients have concurrent MGD as a component of the inflammatory ocular surface disease that characterizes their condition. Regardless of cause, the stasis of oils within the lids as seen in MGD results in an inflammatory response on the ocular surface. At times, this can be so severe as to cause corneal melting or sclerokeratitis.

3. Current and future therapy

Patient education about the natural history and chronicity of the dry eye disorder, and the fact that there are no current “cures”, only treatments, is crucial to successful management of this condition. Alleviation of modifiable factors such as air drafts and humidity of surroundings is essential. Elimination of responsible medications may be considered, if safe, though this is often not practical. The widespread use of computers has lead to increasing awareness of “computer vision syndrome” and ways to address it are promoting the ergonomics of computer workstations, special computer reading aids, and altering work habits. For example, lowering the terminal to

maintain a lower position of the upper eyelid diminishes globe exposure and often helps alleviate symptoms.

Warm compress application on the lids is indicated in patients with meibomian gland dysfunction. We recommend that patients perform this procedure once or twice a day, for at least 10 minutes each time. In patients with severe MGD, warm compresses alone do not suffice, and a course of systemic tetracycline therapy (e.g. doxycycline or minocycline) is often required if there are no contraindications (e.g. pregnancy or allergy) to their use. Use of artificial tears, emulsions, gels, and ointments can be very useful. Nonpreserved tear substitutes are preferable if tears are to be used more than 4 to 6 times a day, to minimize the chances of preserva- tive-induced toxicity to surface epithelial cells. If symptoms or significant surface drying persists despite the above measures, or if the patient is unable or unwilling to instill tears at the required frequency, punctal occlusion can be considered to assist with tear preservation. Silicone punctal plugs are highly effective in aqueous insufficiency, but often undergo spontaneous extrusion. Spectacle side shields, moisture inserts, and moisture chambers are non-invasive therapies that can be used to decrease evaporation, but are often poorly accepted due to poor cosmesis. Surgical approaches are reserved for advanced disease or when there is risk of corneal melting. Severe epithelial disease is treated with bandage contact lenses or autologous serum. If these fail, amniotic membrane grafting to suppress inflammation and tarsorrhaphy may be contemplated. If lid deformities are present, lid surgery is indicated to correct these functional deficits.

a. Anti-inflammatory therapy – Inflammation is seen consistently in different forms of dry eye and dry eye-associated complications, and many patients respond therapeutically to anti-inflammatory treatments. Topical cyclosporine A, a fungal derived molecule used extensively in organ transplantation,

was first used in a canine model of KCS and found to prevent T-cell activation and inflammatory cytokine production. It received FDA approval in early 2003 for patients with severe lacrimal insufficiency, based on an improvement in Schirmer test results and a decrease in ocular irritation symptoms (Gunduz and Ozdemir, 1994; Sall et al., 2000). Cyclosporine also has been found to be helpful in healing paracentral rheumatoid corneal ulceration (Kervick et al., 1992). Topical application of the 0.1% emulsion for up to 3 years has been found to be safe in Phase III studies, although currently only the 0.05% emulsion is commercially available. The most common side effects are burning (11%), stinging upon instillation (4%), and conjunctival hyperemia (3.4%) (Barber et al., 2005). No serious systemic side effects were seen. Corticosteroids can be extremely effective in reducing symptoms and corneal fluorescein staining. Topical corticosteroids are often used before or in conjunction with starting topical cyclosporine therapy, with a brief overlap period of a few weeks. The longterm side effects of corticosteroids, including cataract and steroid response glaucoma, in addition to the heightened risk of infection, preclude their long-term use for management of dry eyes and patients should always be monitored for complications.

4. Future trends in dry eye management

There are a wide number of novel approaches being explored for treatment of DES (see Table 10.1 for partial listing). Much of the attention is being focused on the role of inflammation. Cell adhesion factors (e.g. ICAM-1, integrins, etc.) are being targeted to reduce leukocyte recruitment to the ocular surface. Chemokines and chemokine receptors implicated in dry eye (e.g. CCR5) may be blocked by specific inhibitors to suppress T-cell infiltration into the tissues. Of great interest is the role of tolerance and T-regulatory cells and how they may temper destructive T-cell responses

that participate in the pathogenesis of the chronic disease. Given the importance of hormonal support for exocrine function, and the anti-inflammatory effect of androgens, topical hormonal therapy is being pursued for DES treatment. Finally, there is considerable interest in the role of fatty acids in DES. Tears contain essential fatty acids, both omega-3 and omega-6 which are not manufactured by the body and only obtained through diet. Essential fatty acids are found in various foods, such as flaxseed, black currant seed, canola oil, walnuts, soy, and mainly cold-water fish including mackerel, tuna, salmon, sardines, and herring. A recent study evaluated whether high intake of omega-3-containing foods has a potentially protective role in dry eye. As part of the Women’s Health Study, 32,470 women provided information on diet, and after adjustment for demographic factors, hormone therapy, and total fat intake, this study showed that a higher ratio of omega-6 to omega-3 fatty acid consumption was associated with a significantly increased risk of DES, suggesting that a higher dietary intake

of omega-3 fatty acid may decrease the incidence of DES in women (Miljanovic et al., 2005).

D. Corneal Bacterial Infections/Bacterial

Keratitis

1. Clinical disease

Bacterial keratitis is a common cause of vision loss. Predisposing factors include:

●Contact lens wear (Stapleton et al., 2006)

●Mechanical and chemical trauma

●Chronic ocular surface disease (e.g. dry eye, bullous keratopathy from endothelial dysfunction)

●Immune suppressed state (e.g. HIV infection, topical or systemic immunosuppressive medications including corticosteroids, diabetes)

●Neurotrophic conditions of the cornea (e.g. herpetic infection, diabetes)

●Chronic corneal surface exposure (e.g. lid deformities, neuroparalytic diseases)

●Corneal autoimmune diseases