Anti-Inflammatory and Immunosuppressive Concepts 2

Anti-Inflammatory and Immunosuppressive Concepts
blood cell count; blood pressure. The main known side effects are nephrotoxicity, neurologic symptoms, gastrointestinal symptoms, hyperglycemia, hypomagne- semia, tremor, and hypertension .

Immunosuppressive drugs as outlined above have a broad range of effects; they interact with pathologic immune reactions and should block them effectively. However, a lack of specificity or evolving severe side effects sometimes prevents a therapeutic success. In these situations combination therapy with multiple immunosuppressive drugs is sometimes useful. But with regard to a more specific immune regulatory effect, a lot of monoclonal antibodies or sometimes fusion proteins have been developed which specifically block a receptor. This blockade can downregulate an immune reaction if the blocked molecule has a key function in the pathological immune process. An overview of the substances currently used in patients with autoimmune disorders or in studies .

Biological substances with specificity for TNF-a receptors are frequently used in chronic polyarthritis. It has been noted that TNF-a is one key molecule responsible for destruction of cartilage of joints and blocking of this cytokine receptor will stop inflammation and structural tissue disorganization highly effectively . But aside from joint inflammation, the blockade of TNF-a receptors is also effective in psoriasis, Bechterew's arthritis and inflammatory bowel diseases. Some authors also report beneficial effects of blocking TNF-a receptors in various inflammatory eye disorders .
TNF-a is a cytokine produced by various cells (i.e. monocytes, macro- phages, neutrophils, activated lymphocytes, endothelial cells, fibroblasts, and other cells) . The main function of this proinflammatory cytokine is to induce cachexia and fever. In addition, inflammatory cells will immigrate locally. An increase in synovia cell apoptosis and expression of adhesion mole¬cules takes place. There are two known receptors of TNF-a, one is p55 and the second p75. They are located in the cell membrane and can be cleaved by matrix metalloproteinases. With regard to the eye, we know that TNF-a is expressed in the cornea, especially during inflammation . TNF-a may induce corneal angiogenesis in vivo. There is an interaction between TNF-a and sVCAM-1 . TNF-a may increase NOS2, fibroblast apoptosis, and various MMPs - 1, 3, 10, 11, 13 . TNF-a is elevated in psoriatic skin lesions .

Infliximab is a chimeric monoclonal antibody specific for TNF-a with a humanized Fc part and Fab fragment from mouse. In man the usual dosage is 3-5 mg/kg b.w. intravenously. The interval of treatment should be 0, 2 and 6 weeks and then every 8 weeks afterwards. Etanercept is a fusion protein specific for the p75 receptor of TNF-a. The usual dosage is 25 mg subcutaneously applied twice a week. Adalimumab is another monoclonal antibody fully humanized and specific for TNF-a. The usual application dosage is 40 mg given subcutaneously every 2 weeks. These inhibitors of TNF-a show a very rapid anti-inflammatory response and rare side effects. The clinical efficacy of infliximab is superior to adalimumab and etanercept (personal experience). One has to look for possible infections which may cause lethal complications, especially in cases of tuberculo¬sis. Active tuberculosis has to be ruled out before application of these drugs . Skin reactions may sometimes develop in the area of local application. Possibly myocardial insufficiency may become worse, induction of functional autoanti- bodies and autoimmunity is very rare. The long-term side effects are unclear at present, but an increase in neoplastic disorders is suspected.

Inhibition of the cell surface molecule CD20 is frequently performed in treatment of lymphomas and leukemias. As B cells with CD20 molecules on their cell surface are also involved in a variety of autoimmune disorders, the effect of the monoclonal antibody rituximab, which is able to block the CD20 cell surface antigen, is currently being investigated . At present, favorable clinical results have been reported in the treatment of rheumatoid arthritis or treatment-resistant scleritis due to primary Sjogren's syndrome . However, another study showed no promising effects in Wegener's granulo- matosis with complicated longstanding orbital granulomas . At present it is not clear what medical indication is best for rituximab application.
Severe forms of ocular cicatricial pemphigoid are best treated by systemic Cyc . Local treatment with corticosteroids and CsA is not sufficient , data for a possible effect of subconjunctivally injected mitomycin have not been reported yet, but the risks of that treatment are known, i.e. reduction of limbal stem cells, necrosis of the sclera and ciliary body. Early cases of ocular pemphigoid with moderate activity can be successfully managed with dapsone or related sul- fapyridine substances . But new treatment options have the potential to reduce side effects and seem to be as effective as Cyc. Promising results show daclizumab (antibody against CD25), intravenous immunoglobulins and methotrexate . In addition, surgical treatment may include keratolim- bal allografts and amniotic membrane transplantation in combination with penetrating keratoplasty in cases with sufficient immunosuppression . Presumably, similar drugs will be developed for other disorders in the near future.

Although we have a few guidelines and recommendations for the use of mmunosuppressive substances in general , a lack of controlled studies complicates recommendations, for example for the application of immunosup-pressive substances in Sjogren's syndrome. Therefore, it is still a big challenge which substance or combination's should be applied at what dosages and for how long in an individual patient. This matter is still a difficult task for every physician, even for those experienced in that field. Therefore, further work is still needed on evaluation of objective data for optimal adjustment of treatment. Possibly new options will be available in the future, hopefully with a more specific interaction to correct specifically the immunopathology without changing the physiologic conditions elsewhere in the body.

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Anti-Inflammatory and Immunosuppressive Concepts

Anti-Inflammatory and Immunosuppressive Concepts

Ocular surface disorders do not have to be treated routinely by systemic immunosuppression, as various local treatment options are available and suffi-ciently effective in many patients. These are: (1) lid closure, enable or improve it surgically; (2) local corticosteroids, they suppress local inflammation, but may deteriorate dry eye symptoms and increase risk of local infections; (3) topical cyclosporin A (CsA) acts as an anti-inflammatory with rare side effects; (4) local lubricants, apply them frequently, but be aware of local toxicity resulting in intol-erance to components of these drops (mostly preservatives); (5) vitamin-A-con- taining substances, they improve superficial epithelial cell layers; (6) autologous serum, it contains various cytokines and growth factors as useful adjunct for healing of epithelial defects; (7) therapeutic contact lens, apply it for superficial epithelial defects, but take care of infectious complications; (8) punctum plugs, insert them or obliterate nasolacrimal duct, and (9) amniotic membrane transplantation for reconstruction of superficial layers of the cornea and conjunctiva.

Details of the above-mentioned local treatment options are outlined in chapters 4-9. The use of the various local treatment options were recently rec¬ommended by an international expert panel . There is increasing evidence that dry eye problems beside other pathophysiological disturbances also show increased inflammatory cells and proinflammatory cytokines in the conjunc¬tiva, lacrimal glands and tear fluid . Topical anti-inflammatory substances are therefore a logical therapeutical adjunct. Glucocorticosteroids should be applied only for short time period (2-4 weeks) as they are effective within sev¬eral days, but severe side effects are probable in long-term use . Topical CsA is an anti-inflammatory substance with a slowly acting effect increasing within weeks to 6 months; this substance can be applied topically for a long time, as side effects are very rare .

However, there are some systemic disorders with involvement of the ocular surface and adnexa, where the above-mentioned local treatment options are not sufficiently working. Among these systemic inflammatory disorders are atopic disorders, bullous mucocutaneous disorders with ocular involvement or inflamma-tory disorders due to collagenous or vasculitic systemic diseases. These systemic disorders may show heavy inflammatory involvement of the ocular surfaces and adnexa, therefore systemic anti-inflammatory treatment regimens are reasonable.

The main indications for any systemic immunosuppression are (1) to prevent eyes from becoming blind by inflammation, (2) to maintain the integrity of the eye, and (3) to reduce mortality caused by systemic inflammation. A prerequisite for any immunosuppression is to rule out infection as the possible cause of inflamma¬tion. Immunosuppressive treatment regimens are sometimes shown to be effective in randomized controlled studies, but quite often only uncontrolled case series are available to justify the treatment. In addition, the relative efficacy of different treatment regimens is not determined and interindividual variations of the effectiveness for the same substance is well known for various drugs. Therefore, at present each patient will be best treated with an individualized treatment regimen. In general, the use of alkylating substances often results in long-term drug-free remissions, but treatment with other substances needs to be continued long term or even indef¬initely. A guideline gives advice how to manage this topic .

First-line anti-inflammatory treatment consists of corticosteroids, which can be applied topically, periocularly or systemically. Their anti-inflammatory capac¬ity becomes evident within a few days. However, side effects, possible complica¬tions, or sometimes ineffectivity limit their application. Usually, in patients with liver insufficiency about 1mg/kg/day prednisolone is applied, and in severe inflammation pulses of 1 g/day for 3-5 days are possible. The dose should be reduced stepwise (10 mg every 1-2 weeks, at the level of 40mg/day reduce in 5-mg steps, at 20mg/day in 2.5-mg steps, at 10 mg in 1-mg steps), reduction intervals can be prolonged from 1 to 4 weeks depending on the clinical course. During glucocorticosteroid treatment, monitoring of hypertension, body weight, blood glucose (every 3 months), serum lipids, density of bones (once a year) should be performed. Important and frequent side effects are (a) increased risk of infection, (b) fluid retention, (c) diabetes mellitus, (d) hyperlipidemia, (e) osteo¬porosis, (f) atherosclerosis, (g) glaucoma, (h) cataract, (i) anxiety, (j) sleepiness, (k) mood changes, (l) easy bruising, and (m) poor wound healing. As supple¬ments to steroids, calcium 1,500 mg/day, vitamin D 800IU/day, estrogens, if decreased or postmenopausal, and antiabsorbants should be added. Adverse effects of glucocorticosteroids are cushingoid changes (weight gain, moon facies, fat redistribution, acne) for doses >5-10 mg/day prednisone, uppression of adrenal glands, and delay of pubertal growth in children. Sometimes severe side effects such as pancreatitis, aseptic bone necrosis, IDDM, myopathy, or psychosis require immediate reduction of corticosteroids. In cases of concomitant use of NSAID, the risk of gastric ulceration increases. Long-term corticosteroid therapy is associated with an increase in mortality. If corticosteroids fail to induce improvement of the inflammation within 2-4 weeks or if a continuous dose of > 10 mg/day is needed, then additional systemic immunosuppression with alter¬native drugs should be performed . The immunosuppressive substances fre¬quently applied in such human disorders are outlined.

Cyclophosphamide (Cyc) is a cytotoxic alkylating drug. It effects resting and dividing lymphocytes and results in a broad T- and B-cell impairment. The drug is well absorbed and metabolized in the liver. It is eliminated via the kid¬neys and therefore some metabolites can cause bladder toxicity. The main indi¬cations for Cyc are as antineoplastic drug in oncology, in autoimmune disorders especially SLE and Wegener's granulomatosis, uveitis and ocular cicatricial pemphigoid. Usually a dose of Cyc of 1-3 mg/kg/day is given. Pulse treatment every 3-6 weeks of about 600-1,500 mg is a possible alternative. The main side effects are bone marrow depression, rarely myelodysplasia, hemorrhagic cysti¬tis, teratogenicity, ovarian suppression, testicular atrophy, azospermia, alopecia, nausea, vomiting, and opportunistic infections due to lymphopenia. Routine monitoring of blood cell count, platelets, urinalysis, every week initially and later every month is recommended .

Chlorambucil is a cytotoxic alkylating drug inducing crosslinking of DNA to proteins. It is metabolized in the liver to phenylacetic acid mustard. Inactive compounds will be eliminated in the urine. Indications are as antineoplastic drugs in oncology, Behcet's disease, uveitis especially due to Behcet's syndrome and sympathetic ophthalmia. The dosage should be 0.1-0.2 mg/kg/day for about 1 year. Alternatively a short-term (3-6 months) treatment is possible with initiation of 2 mg/day and an increase every week by 2 mg until complete suppression of inflammation or white blood cells are <2,400/^1 or platelets < 100,000/^l are reached. The side effects are bone marrow suppression, mostly reversible, but often prolonged, opportunistic infections (e.g., herpes zoster, Pneumocystis carinii), permanent sterility in men and amenorrhea in women, teratogenicity, increased risk of malignancy in the long term. Monitoring of blood cell counts every week initially, later monthly, in cases of short-term regimen every week is advised . Azathioprine (Aza) interferes with adenine and guanine ribonucleotides resulting in reduced numbers of lymphocytes, mixed lymphocytes reactivity, IL- 2 synthesis and IgM production. The substance is orally well absorbed; metabo¬lism of Aza needs activity of xanthine oxidase, which can be inhibited by allopurinol. The main general indications are rheumatoid arthritis, organ trans¬plantation, psoriasis, Reiter's syndrome, or systemic lupus erythematosus; in ophthalmology, chronic uveitis, uveitis in Behcet's syndrome and intermediate uveitis are frequent indications. The dosage ranges between 1 and 3 mg/kg/day, reduction is recommended when allopurinol is applied. The main side effects are reversible bone marrow suppression, increased risk of non-Hodgkin's lym¬phoma, hepatotoxicity 2%, and gastrointestinal intolerance 25%. Monitoring of blood cell counts and platelets at 4- to 6-week intervals and liver enzymes every 12 weeks is recommended. The dosage should be reduced if liver enzymes increase >1.5-fold, stop Aza application if the rise is >5 times of normal .

Mycophenolate mofetil (MMF) selectively inhibits inosine monophosphate dehydrogenase, it reduces lymphocyte proliferation, suppresses antibody synthe¬sis, reduces cellular adhesion to vascular endothelium, and inflammatory cell recruitment. MMF shows renal elimination and has a high oral bioavailability. The main indications are transplantation of solid organs, uveitis, and scleritis. However, no controlled studies are available. In most cases, MMF reduces ocu¬lar inflammation if applied with other immunomodulating substances. The rec-ommended dosage is 2 X 1 g/day. The main side effects are gastrointestinal pain, nausea, vomiting, and diarrhea in up to one third, rarely infections, and neoplas- tic disorders. One should monitor blood cell counts every week for the first month, later at 2-month intervals, and liver enzymes at 3-month intervals .

Methotrexate (Mtx) is a folic acid agonist inhibiting dihydrofolate reduc- tase. It inhibits rapidly dividing cells. Oral absorption is reduced by metaboliza- tion of the drug by intestinal flora in up to one third, parenteral application is therefore much safer. Addition of 1 mg/day folate reduces nausea. Patients should abstain from alcohol consumption during treatment. The substance is eliminated by the kidneys. The main indications for Mtx are rheumatoid arthri¬tis, juvenile chronic arthritis, psoriasis arthritis, systemic lupus erythematosus, several neoplastic disorders, uveitis, scleritis, orbital pseudotumor. Major side effects are cytopenia, hepatotoxicitiy, interstitial pneumonia, stomatitis, and nausea. Mtx is contraindicated during pregnancy. During treatment one should monitor blood cell counts and liver enzymes at 1- to 2-month intervals .

CsA inhibits preferentially immunocompetent T lymphocytes. CsA is metabolized in the liver and excreted in the bile. Bioavailability of CsA shows a broad range. The main indications are solid-organ transplantation, treatment- resistant rheumatoid arthritis, severe plaque psoriasis, uveitis, and Behcet's syn-drome. The currently recommended dosage is 2-5 mg/kg/day. Serious side effects include nephrotoxicity, hypertension, less common hepatotoxicity, gin- gival hyperplasia, myalgia, tremor, paresthesiae, hypomagnesemia, and hir- sutism. It is recommended to monitor blood pressure often, at least every month, serum creatinine every 2 weeks for 2 months, then monthly. Detection of CsA blood levels is not necessary .

Tacrolimus (FK-506) inhibits activation of T lymphocytes. The absorption of the drug from gastrointestinum varies. Tacrolimus is metabolized by the cytochrome P450 system and shows mainly fecal elimination. Indications for FK-506 are solid-organ transplantations, and uveitis, although only small num¬bers of patients have been reported. The dosage is usually 0.1-0.15 mg/kg/day for transplantation and 0.05 mg/kg/day for uveitis, respectively. During treat¬ment, monitor drug blood concentration weekly for about 2 months, then monthly; test liver enzymes, bilirubin, blood urea nitrogen, creatinine, electrolytes including calcium, magnesium, phosphate; cholesterol, triglycerides, glucose

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Medical Management of Dry Eye Disease-Identify and Treat Associated Conditions

Medical Management of Dry Eye Disease-Identify and Treat Associated Conditions
Local Factors Associated with Dry Eye
These factors include: (i) Posterior lid margin disease (blepharitis) may exacerbate evaporative dry eye. This may be associated with rosacea and aller¬gic eye disease. (ii) Corneal exposure from lagophthalmos, lid margin defects, or seventh nerve palsy allows excessive evaporation. Abnormal globe position, lid retraction or exophthalmos from thyroid eye disease should be treated. (iii) Relative corneal anaesthesia with reduced reflex tearing following LASIK may precipitate dry eye symptoms.

Systemic Disease
A number of systemic conditions also cause ocular surface disease and severe dry eye, although dry eye disease is rarely the presenting symptom. These conditions should be investigated and treated appropriately, but the treatment of the associated dry eye disease is then usually still based on ocular signs rather than the underlying condition. These diseases include: (i) Sjogren's syn¬drome; (ii) rheumatoid arthritis; (iii) scleroderma (crest syndrome - calcinosis,
Reynaud's phenomenon, oesophageal hypomotility, sclerodactyly, and telang-iectasia); (iv) systemic lupus erythematosis; (v) retroviral infection: infection with HTLV1, HIV, hepatitis C, or chronic Epstein-Barr virus (EBV) infection - EBV infection has been proposed as a trigger for the onset of Sjogren's syn¬drome, and (vi) cicatricial conjunctivitis (mucous membrane pemphigoid, Stevens-Johnson syndrome, atopic keratoconjunctivitis, graft-versus-host disease).

Tear Substitutes
These have a relatively simple formulation compared to normal tears and their delivery is periodic rather than continuous. Although continuous delivery pumps are available, they are usually restricted to the treatment of extreme dry eye. The relative contribution of their individual components to the overall desired effect - lubrication, replacing tear components, reducing osmolarity, or diluting inflammatory agents - is difficult to prove. Slightly alkaline pH drops are better tolerated than neutral or acidic drops . Almost all artificial tears aim to replace the aqueous phase of the tear film. There are no mucus substi¬tutes, and oils and lipids are only an approximation to the action of tear lipid layer. Simple electrolyte solutions and saline are rapidly lost from the ocular surface and attempts have therefore been made to increase the ocular surface residence time by adding macromolecules that increase the viscosity or gel properties of the solution, contribute a demulcent effect, and potentially com¬bine with the mucus component of the tear film . These viscous or gel agents are otherwise inactive components of the drop. For example, the ocular surface residence time of arboxymethylcellulose is significantly longer than smaller molecule hydroxypropylmethylcellulose, although it is uncertain whether this fact fully explains the difference in effect. Because relative effi¬cacy or artificial tear drops is difficult to compare the principal categories are listed in alphabetical order .

(1)Acetylcysteine 5% drops are commercially available and are useful in patients with filamentary keratitis and mucous plaques secondary to dry eye. They are used 4 times daily and may cause stinging following instillation if there is epithelial disease. Acetylcysteine 10 and 20% is not available commer¬cially and they have a limited bottle life even if kept refrigerated.

(2)Cellulose-based products have been the mainstay of artificial drop treatment for years. Except for carmellose they have a short ocular surface res-idence time.
(3)Carbomers 974P and 980 make a relatively viscous solution, which increases ocular residence time.

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Medical Management of Dry Eye Disease - Mechanical Behaviour of the Tear Film

Medical Management of Dry Eye Disease - Mechanical Behavior of the Tear Film
Fluids can be classified according to the way they behave under sheer stress. A perfect fluid has no resistance to shear stress and therefore lacks vis¬cosity. Fluids that are not perfect are classified as either newtonian if their viscosity is constant for different rates of shear, or non-newtonian if they become less viscous over time when a shear force is applied. This property of non-newtonian fluids is termed thixotropy - these are fluids that are both viscous and elastic. Tears have thixotropic properties but most artificial tears do not. The linear charged polymers (carboxymethylcellulose and hyaluronic acid) are the only agents used in artificial tears that have shear-thinning characteristics of non-newtonian fluids. It has been proposed that tears behave like a fluid during blinking but more like a gel between blinks.

Regulation of Tear Film Components
Regulation of the stability of the tear film is under hormonal and neuronal control. Androgen receptors have been identified in meibomian tissue, while oestrogen and progesterone receptors have been identified in conjunctiva and lacrimal gland . Postmenopausal women and the elderly may be relatively androgen-deficient and this may account for some of the involutional changes seen in periocular tissue.

Androgens (testosterone) may also act as a natural suppressor of inflammation . Hormone treatments have been evaluated to treat some of the involutional changes associated with dry eye disease. Nerve fibres have been demonstrated adjacent to the lacrimal gland, goblet cells, and meibomian glands. The role of these fibres in maintaining the tear film is unclear although parasympathetic (acetylcholine- and VIP-dependent) fibres stimulate aqueous and protein secretion from the lacrimal gland, and VIP end¬ings at the basement membrane may stimulate mucus secretion from the goblet cells.

Inflammation and Dry Eye Disease
A T-lymphocyte infiltrate is present in the conjunctiva and accessory glands of 80% of patients with dry eye disease. There is also an increased expression of HLA class II antigens, markers of apoptosis (Fas-Fas ligand), and inflammatory cytokines in the epithelium. Although this is thought to be a pri¬mary event in Sjogren's syndrome, secondary inflammation from surface fric¬tion during blinking is probably an aggravating factor in the majority of patients with dry eye disease. Inflammation may thus be both the cause and the result of dry eye, amplifying and perpetuating disease. The presence of inflammation is the rationale for the use of steroid and immunosuppression in the treatment of dry eye disease in patients with and without Sjogren's syndrome .

Guidelines for Clinical Management
Dry eye disease is generally not curable and management is structured around the control of symptoms and the prevention of surface damage. Clinical tests have a low sensitivity and specificity and they are not a reliable basis for management. Fortunately, in the great majority of patients the disease is not sight-threatening. The choice of treatment depends on the severity of the dis¬ease, and one or more of the following measures may be used alone or in com¬bination. Initial treatment is with artificial tears that lubricate the surface and reduce lid friction, although they usually only provide relief for a short time period after drop instillation. The goal of treatment is to improve eye comfort and vision at a frequency of treatment that can be reduced to a minimum. Guidelines have been produced to indicate the level of management that is appropriate according to the severity of disease . There is a placebo effect and some patients wish to continue using artificial tears without clinical signs of dry eye. A benefit with regard to patient symptoms is more difficult to achieve than a resolution of ocular signs .

General Measures
(1)Patient education. Discuss the nature of the condition to establish a realistic expectation of outcome, provide reassurance, and encourage compli¬ance with treatment.

(2)Review of the home and work environment. Emphasize the importance of blinking when reading or using a video display unit. Eliminate dry air condi¬tioning and wind if possible. A reduction in room temperature and central heat¬ing will minimize tear evaporation. Humidifiers are usually disappointing because they do not increase room humidity sufficiently. Working directives and open plan offices can limit the ability of employers to implement these rec¬ommendations. A local increase in humidity can be achieved with moist cham¬ber goggles or side shields to glasses if this is cosmetically acceptable.

(3)Discontinue toxic topical treatments if possible. Numerous systemic treatments have been associated with symptoms of dry eye, e.g. thiazide diuret¬ics, anticholinergics, tricyclic antidepressants, ^-blockers, isotretinoin (13-cis- retinoic acid), and antihistaminines (loratadine, cetrizine). The excipients (e.g. benzalkonium chloride, EDTA) in drops used for other reasons, e.g. glaucoma medications, may aggravate surface damage. The preservative benzalkonium chloride can be particularly toxic to the epithelium.

(4)Aids should be provided for patients with a loss of dexterity (e.g. rheumatoid arthritis). Single unit dose dispensers for preservative free drops may not be appropriate. Stiff plastic dropper bottles can be held and squeezed in a nutcracker or an eyedrop bottle squeezer (available commercially).

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Medical Management of Dry Eye Disease

Medical Management of Dry Eye Disease

The initial management of dry eye disease relies on the use of artificial tear substitutes and the conservation of natural tears. Most artificial tears are lubricants with an electrolyte content that is only an approximation of normal tears. Viscosity agents are often added to artificial tears to increase the ocular surface residence time. An understanding of the complex interactions between aging, hormonal change, the environment, and the immune system has lead to new therapies to treat dry eye disease. Treatments that reduce associated conjunctival inflammation and stimulate the production of normal tear components may become increasingly important for the management of severe disease. An understanding of the behaviour of normal tears and the aetiology of dry eye is fundamental to the development of an effective treatment strategy.

Rational for Medical Management
Structure of the Tear Film
The tear film is part of a functional unit that comprises the tears, corneal and conjunctival epithelium, lacrimal glands, and lids. Disturbance of one or more of these interrelating structures can result in characteristic symptoms and signs of dry eye disease. This disease acts through the common disease mecha¬nisms of hyperosmolar tears and surface drying that damages the epithelial cells, with associated inflammation and a susceptibility to infection. The terms dry eye disease, dysfunctional tear syndrome, and keratoconjunctivitis sicca are synonymous.
Tears are mechanically spread over the ocular surface by upper lid blink¬ing, but the development of an effective tear film depends upon surfactant phospholipids in the surface layer and mucous in the basal layer that allows the fluid to adhere to the hydrophilic epithelial cells. The lubricating action of the tear film disperses the shearing forces on the epithelium caused by blinking. Finally, the tear film provides a smooth optical interface, transports metabo¬lites, and freely transmits oxygen and carbon dioxide to the cornea.

The structure of the tear film consists of an outer lipid layer lying on an aqueous layer that contains mucus. The meibomian glands secrete the lipid, which is released from the glands by lid movement. The lipid layer is composed of two phases: (1) an outer surface non-polar phase that contains waxes, choles¬terol esters, and triglycerides and (2) an inner polar aqueous-mucin phase that has surfactant properties. The inner polar phospholipids are bound to protein lipocalins within the aqueous layer that bind hydrophobic molecules and con¬tribute to tear viscosity. The lipid layer reduces evaporation from the aqueous layer and dysfunction may result in an evaporative dry eye state .

The aqueous layer is secreted by the main and accessory lacrimal glands and consists of water, electrolytes, dissolved mucins, and proteins. It has antibacterial properties due to the presence of IgA, lysozyme and lactoferrin, and it contains growth factors (EGF, TGF-a, HGF) secreted from the lacrimal gland in response to injury . It also contains leukocytes and pro-inflamma¬tory cytokines that accumulate when tear production is reduced during sleep. The aqueous phase can physically wash away debris and toxic agents that may cause inflammation. Deficiency of this layer results in an aqueous deficiency dry eye .

Mucins are at their highest concentration internally in the aqueous phase and they serve to increase viscosity and anchor the aqueous phase to the glyco- calyx of the external cells of the epithelium. Each mucin is a high-molecular- weight glycoprotein containing a protein core with radially linked carbohydrate side chains. The protein core forms the basis of further classification (e.g. MUC1, MUC2, etc.). Human mucins are classified according to anatomical distribution as transmembrane or secretory, and the secretory mucins are fur¬ther classified according to their physical properties as gel-forming or soluble. Secretory ocular mucins are principally produced by the conjunctival goblet cells (MUC5AC) but also by the lacrimal glands (MUC7). The glycocalyx of the superficial epithelial cells of the cornea and conjunctiva is formed of trans¬membrane mucins (MUC1, MUC2, and MUC4). MUC1 is essential to aid spreading of the secretory gel mucin produced by goblet cells and it also pre¬vents pathogens binding to the ocular surface . Damage to the mucus-binding complex will change the cell membrane from a hydrophilic to a hydrophobic surface and prevent normal tear film adherence. Loss of goblet cells and ocular surface mucus is a feature of cicatrising conjunctivitis, vitamin A deficiency, and chemical burns. Almost all of this complexity of structure is absent from artificial tears.

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General Information and Recommendations

General Information and Recommendations

Diagnostic tests of dry eye states are in general intended for two groups of patients: those who come for the first visit with a suspected dry eye and those who have already undergone therapy elsewhere and wish further advice. In the
first group of patients the test series for dry eye can be started immediately. In the second group of patients it is recommended to stop the patients' preexisting therapy for 1 week and start the testing after wards. This opens the pathway towards an exact diagnosis without any therapeutic interference.

For the routine diagnostic way of a suspected dry eye state it is advised to select a number of tests. Non-invasive procedures like questionnaires, symptoms and history and slit-lamp examination are among these and often are called low-tech diagnostic. Considering patients' comfort and economic aspects, simple tests should always be used. These tests provide already a reliable information of the dry eye condition. A questionnaire has a surprisingly high sensitivity of 77% with a specificity of 81% . In combination with data from other non-invasive methods, sensitivity and specificity can even be raised. Slit-lamp characteristics like an irregularity of the black line or hyper- aemia of the conjunctiva result in a sensitivity of 92% and a specificity of 81% . Simple low-tech diagnostic is therefore the basis of the dry eye testing.

Besides that, a battery of dry eye tests exist which are mildly or markedly nvasive. The order of tests is of critical importance since one test may influence the result of the next. Therefore it is recommended to start with the least invasive test and to end with the most invasive procedure. Some tests are mutually exclusive, which means that in a certain patient only a selection of dry eye tests is performed.
Within this system of tests (table 2) with increasing invasiveness, intervals of 5 min are recommended between invasive tests. This is the time necessary for restoration of the original meniscus height . For the routine dry eye patient a sequence of tests giving the essential information for the classification should be selected .

After having selected the appropriate combination of tests, the grading and interpretation of these tests gains importance. It is essential to know the informa¬tion we can get from a certain test in order to classify our patient's dry eye form as tear-deficient or evaporative. If you suspect a hyperevaporative dry eye the non-invasive BUT and meibography should be measured. Meniscometry and Schirmer I test are specifically indicative for the hypovolemic dry eye. The same tests give us sufficient information about the severity of the ocular surface disease. Staining with Lissamine and fluorescein allow a more precise quantification of the severity and are therefore recommended . The interpretation is based on agrading system of the tests mentioned above. This system allows us to distinguish normal from marginal dry eyes or manifest dry eye patients.

Once the diagnosis is confirmed and the grade of the disease established the patients need follow-up examinations. The course of the KCS under therapy is documented. We get the best information from a repetition of the tests which have been selected initially. This pathway of examination provides reliable information about the course of the disease and forms the basis for longitudinal observations. However, we have to take into account that certain tests like fluorescein and rose bengal staining show limits with respect to their reliability at different times. Nevertheless, these tests are necessary to provide exact information about the localization of ocular surface defects, whereas the non-invasive tests give us broader information about the whole ocular surface. The diagnosis of dry eye is therefore based on the data of different tests with increasing invasiveness arranged in a way to minimize interference between the tests and on the grading of the results which permit a selection of the appropriate therapy and a long-term obser¬vation of the patient.

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Diagnosis of Keratoconjunctivitis Sicca-Fluorescein Tests

Diagnosis of Keratoconjunctivitis Sicca-Fluorescein Tests

Fluorescein sodium is used for several dry eye tests . They all are mildly invasive tests. At a concentration around 0.1%, the dye is highly fluorescent, staining the tear film and epithelial defects. Once the surface layer of epithelial cells is lost, the dye spreads rapidly in the intercellular space. Fluorescein is available in the form of fluorescein-impregnated paper strips or as a 1-2% solution in a sterile, unit dose sachet. Fluorescence is with the use of a blue exciter filter in combination with a yellow barrier filter. Most slit-lamps are provided with an adequate blue light source and it is well worth purchasing a suitable Kodak Wratten 12 or 15 barrier filter.

To instil fluorescein from an impregnated strip, a drop of sterile saline is applied to the impregnated end and the excess discarded with a rapid flick. The moistened tip is then touched lightly onto the lower tarsal plate of the right and then the left eye, in sequence. Because 1-2% fluorescein is non-fluorescent, it is only appropriate to apply a small volume in order to achieve dilution and flu¬orescence. A suitable volume is 2-5 |xl applied with a micropipette.

The fluorescein tear film break-up time records the rupture of the tear film after a blink. The tear film should be evaluated after a few blinks. The average of three measurements provides a representative measure of the tear film stabil¬ity . Evaluation: >10 s: normal; 5-10 s: marginal dry eye; <5 s: dry eye.

Fluorescein staining of the interpalpebral surface of the eye has a character¬istic pattern in KCS, initially affecting the lower part of the exposed eye and later affecting the cornea and conjunctiva more extensively. In meibomian gland dys-function the staining pattern is often disposed over the lower cornea, closer to the lower lid margin. A number of suitable grading schemes exist . The Oxford grading scheme consists of a series of panels representing the cornea and the two zones of exposed conjunctiva, on which is displayed a pattern of dots representing increasing staining from grade 0 to 5 (fig. 8). The number of dots increases sequentially in a log-linear scale: from grade 0 to 1 there is a 1-log step,

which means that 10 dye spots are detected per 1 zone in grade 1. Between grade 1 and 5 there is a 0.5-log unit increase of spots, which equals 32 dye spots in grade 2, 100 dye spots in grade 3 and 316 dye spots in grade 4, always counted per 1 zone. Grade 5 is detected, when the number of dye spots exceeds 316 per 1 zone. The individual scores for each of the 3 panels are added up to give the total score. The maximum staining score for the exposed conjunctiva and cornea is 15.

An important point to note is that if the recommended filter combination is used then grading with fluorescein can be carried out on both the cornea and conjunctiva and use rose bengal can be avoided. This prevents patient discom¬fort, since in the absence of an anaesthetic, rose bengal causes intense stinging on instillation (fig. 9). Staining of the epithelium can occasionally be obscured by the fluorescence of the tear film. Asking the patient to blink several times allows the staining pattern to be viewed more clearly.

The stained meniscus can be used to estimate the meniscus volume, either simply by measuring meniscus height using the width of the slit-lamp beam, or in a more sophisticated fashion, by reflective meniscometry or by assess¬ing its profile photographically in slit section . A meniscus radius of curva¬tures <0.25 mm suggests a dry eye condition.

Fluorescein can also be used for measurements of tear turnover and of the tear fluorescein clearance .

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Diagnosis of Keratoconjunctivitis Sicca

Diagnosis of Keratoconjunctivitis Sicca
The above definition of the dry eye accentuates the following features of the disease: (1) symptoms; (2) interpalpebral surface damage; (3) tear instabil¬ity, and (4) tear hyperosmolarity. There are numerous tests for the diagnosis of dry eye and they vary with respect to their invasiveness. The selection and order of these tests is of paramount importance since each test may influence the out¬come of the test which follows. In general it is recommended to start with the least invasive procedure and to end with the most invasive test. Occasionally it is necessary to perform some tests on a subsequent day. At the end of a battery of tests it should be possible to confirm the diagnosis, classify the form of dry eye, being conscious of its grade, and initiate appropriate therapy.

Symptoms and History
A record of clinical history and ocular symptoms is required. Several ques-tionnaires have been developed for the assessment of dry eye . A special questionnaire for the detection of psychosomatic alterations exists and can be applied additionally .

Important aspects of the patient's history are: (a) symptoms: burning sen-sation, foreign body sensation, tired eye, photophobia, epiphora, swelling of the lids; (b) onset of the symptoms, duration; (c) circadian rhythm; (d) environmen¬tal conditions at home and in the office (smoke, wind, humidity); (e) contact lens-associated problems; (f) cosmetics; (g) systemic diseases; (h) allergic dis¬eases; (i) dermatologic diseases, and (j) drug history.

Examination of the Lids
The dynamics of blinking and of lid position should be observed whilst taking the history in order to prevent conscious alterations. Points of interest are: (a) frequency of blinking; (b) variation of blink intervals; (c) size of the palpebral aperture, and (d) adequacy of lid closure.

The position of the lids may influence the tear turnover, therefore care should be taken to identify the following malpositions: (a) entropion; (b) ectro- pion; (c) eversion of the lacrimal puncta; (d) cicatrical malposition; (e) derma- tochalasis, and (f) swelling of the temporal aspect of the upper lid, implying enlargement of the lacrimal gland.

Slit-Lamp Examination
Slit-lamp biomicroscopy should evaluate the following anatomical structures and their alterations: (a) Lid margins: hyperaemia, telangiectasia, thickening, scar-ring, keratinization, ulceration, tear debris, abnormalities of the meibomian

orifices, metaplasia, character of expressed meibomian secretions. (b) Eyelashes: misdirection, malposition, encrustations, collarettes. (c) Conjunctiva: erythema, swelling, keratinization, papillary/follicular reaction, pinguecula, lid parallel con-junctival folds. (d) Cornea: infiltrates, scars, punctuate staining or ulcers, vascu-larization, pannus, and pterygium. (e) Additionally, the tear film should be analysed for: filaments, mucus, and cellular debris, meibomian foam.

Non-Invasive Break-Up Time
The non-invasive break-up time test was created to measure the stability of the precorneal tear film without any dye . It involves projection of a target onto the convex mirror surface of the tear film and recording the time taken for the image to break up after a blink. The test was originally performed with a custom-built 'Toposcope' but has also been performed over a limited zone of the exposed precorneal film, using a keratometer. It can also be measured with the TearscopePlus™ and is a non-invasive procedure .

Interferometry
Tear film interferometry is a non-invasive technique for grading the behav¬iour of the tear film lipid layer and estimating its thickness on the basis of the observed interference colours (fig. 4). It is useful for selecting dry eye
candidates for punctal occlusion. Apparatus which have been used for this pur¬pose include the TearscopePlus and the Kowa DR-1.
A colour scale which has been used is as follows : (a) greyish colours, uniform: normal; (b) greyish colours, non-uniform: normal; (c) yellow colours: dry eye; (d) brown colours: dry eye, and (e) blue colours: dry eye.

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