Allergic and Immunologic Diseases of the Eye PDF

SECTION D The Eye 38 Allergic and Immunologic Diseases...

SECTION D The Eye 38 Allergic and Immunologic Diseases of the Eye Neal P. Barney CONTENTS Introduction, 605 Conjunctival Provocation Testing, 614 Anatomy and Physiology of the Eye, 605 Contact Dermatitis, 615 Allergic Diseases of the Eye, 606 Other Immunologic Diseases of the Eye, 616 and treatment of these disorders. Nonallergic ocular diseases with SUMMARY OF IMPORTANT CONCEPTS immunologic implications will be discussed with reference to the prin- The eye is a unique organ because of its varied tissue types, accessibility cipal anatomic structures affected. to direct examination, and direct connection to the central nervous system. Allergic eye disease includes clinical disorders that have different ANATOMY AND PHYSIOLOGY OF THE EYE severities. Allergic conjunctivitis (AC), demonstrates minimal changes such as an Topographic Anatomy increase in mast cell activation, minimal presence of migratory inflammatory Figures 38.1 and 38.2 demonstrate the ocular anatomy pertinent to the cells, and symptoms mostly from the effects of mast cell mediators. discussion of the allergic and immunologic diseases of the eye. The eye The more chronic forms of allergic eye disease such as atopic keratocon- and its adnexa lie within the bony orbit. The thinnest portion of the junctivitis (AKC) and vernal keratoconjunctivitis (VKC) demonstrate persistent bony orbit is found medially. This portion of the orbit is critical, because mast cell, eosinophil, and lymphocyte activation; increased mucosal-type pathologic thinning of the bone may allow spreading of infections, (MCTC) mast cells; mild to moderate corneal pathology; and development inflammatory diseases, and neoplasms starting in the sinuses through of conjunctival scar and fibrosis. These changes are responsible for the the bone into the orbit. vision-threatening risk associated with these diseases. Nonallergic immunologic disorders of the eye are less well defined than Lacrimal System allergic eye diseases. In general, nonallergic, inflammatory diseases of the The main and accessory lacrimal glands produce the aqueous portion eye are driven by types 2, 3, and 4 hypersensitivity reactions with more of tears. The main lacrimal gland has two portions: the orbital portion vision threat secondary to the involvement of the more delicate intraocular lies in a shallow depression within the frontal bone. The palpebral structures such as the choroid and retina. portion, or portion that overlies the globe itself, may be seen in the superior temporal quadrant by elevating the upper lid off the globe (Fig. 38.2). The ductules conveying the aqueous tears to the ocular INTRODUCTION surface open in the superior fornix. The fornix is formed where the conjunctiva lining the underside of the upper eyelid is reflected Many systemic disorders have ocular manifestations. Allergic eye diseases onto the globe (Fig. 38.2). The accessory lacrimal glands are located principally affect the conjunctiva and are most typically found in indi- in the fornix. They are histologically identical to the main lacrimal viduals who have an allergic background. Other diseases of the eye with gland. purported immunologic mechanisms may not have any systemic disease The aqueous portion of tear fluid (also called tear film) is admixed associated with the eye disease. This chapter will focus on the five well- with both mucin and lipid components. The mucin component is derived defined entities that constitute allergic eye disease and other diseases from goblet cells contained within the conjunctival epithelium and of the eye thought to have an immunologic basis. To put into perspective from the epithelial cells themselves. The lipid portion is secreted onto the discussion of these ocular disorders, the first section of this chapter the ocular surface from meibomian glands. Inflammatory conditions will describe the pertinent anatomy and physiology of the eye. Subse- may alter the volume or composition of any of the three components quent sections will detail the clinical manifestations, pathophysiology, of tear film. The surface of the eye has a tear volume ranging from 2.6 605 606 SECTION D The Eye Lacrimal gland Lateral horn of (orbital lobe) the levator aponeurosis Punctum Ampulla Canaliculus Ductules Lacrimal sac Middle meatus Middle turbinate Lacrimal gland Inferior (palpebral lobe) turbinate Nasolacrimal duct Inferior meatus Fig. 38.2 Cross-sectional anatomy of the eye. Fig. 38.1 The lacrimal drainage system. (From Nerad JA. Techniques in ophthalmic plastic surgery: a personal tutorial. 1st ed. Philadelphia: Immunoglobulins and complement components diffuse from the limbus Elsevier Health Sciences; 2009.) into the cornea. Sclera to 7.4 microliters. The normal turnover rate of tears on the ocular The optically clear, avascular cornea blends into the white sclera at the surface is 12% to 16% per minute. Most commercially available eye limbus. The sclera is the dense connective tissue structure responsible drops will dispense (in a single drop) a volume that far exceeds the for the form and strength of the globe (Fig. 38.2). It may be possible volume held by the ocular surface. A therapeutic drop instilled into the to distinguish clinical entities of episcleral and true scleral inflammation eye is about 30 microliters and would completely displace the tear based on the response of these plexi (see Episcleritis and Scleritis). volume and be cleared by tear turnover in 5 to 10 minutes, and the These plexi become intermingled with each other and the conjunctival excess volume would come out of the eye with first blink following vasculature most notably near the limbus. instillation. Accordingly, it would only be necessary to prescribe admin- istration of a single drop at each time. Uvea The uvea is the middle and most vascular structure of the eye (Fig. Eyelids 38.2). It begins anteriorly as the iris, becomes the ciliary body, and The eyelids, a composite structure of skin and its appendages, muscle, then the choroid as the vascular tissue sandwiched between the outer and connective tissue, are lined by conjunctiva (Fig. 38.2). The skin sclera and inner retina. The choroid extends posteriorly from the begins near the eyelid margin at the mucocutaneous junction. Cranial ciliary body throughout the eye (Fig. 38.2). This almost entirely vas- nerve VII innervates this muscle that functions in proper closure of cular structure serves the metabolic needs of the outer aspect of the the eye. The levator muscle, innervated by cranial nerve III, inserts into retina. the superior margin of the superior tarsal plate. Retina and Optic Nerve Conjunctiva The retina is the neurosensory light receptor layer of the eye. The outer- The conjunctiva is a mucous membrane that begins at the eyelid margin, most portion contains the photoreceptor layer of rods and cones. The lines the posterior portions of the eyelids (tarsal conjunctiva), and is middle cell layer (the bipolar layer) receives synaptic connections from reflected onto the globe (bulbar conjunctiva). From this reflected area the photoreceptors and sends axonal connections to the ganglion cells. (the fornix) the conjunctiva moves anteriorly, covering the globe up to The ganglion cell layer sends its axons to the optic disc, where they the limbus, the anatomic junction of the cornea and sclera (Fig. 38.2). coalesce as they exit the eye forming the optic nerve. A branch of the Mast cells are most numerous near the limbus. The conjunctiva is capable ophthalmic artery serves the optic nerve, courses forward, and branches of containing significant amounts of fluid (chemosis). The lymphatic within the eye as the retinal artery with venous return pathways aligned drainage of the conjunctiva is partitioned and tends to be to the pre- with the arteries. auricular or submandibular nodes. Cornea ALLERGIC DISEASES OF THE EYE The cornea is the avascular, most anteriorly placed portion of Allergic eye disease is typically divided into five distinct types: allergic the eye (Fig. 38.2). It is composed of stratified squamous epithe- conjunctivitis subdivided into seasonal and perennial allergic conjunc- lium, a stroma, and a single layer of nonreplicating endothelium. tivitis (SAC and PAC, respectively), atopic keratoconjunctivitis (AKC),  CHAPTER 38 Allergic and Immunologic Diseases of the Eye 607 vernal keratoconjunctivitis (VKC), and giant papillary conjunctivitis Epidemiology. Prevalence estimates for allergic conjunctivitis are dif- (GPC). Giant papillary conjunctivitis is considered an iatrogenic form of ficult, because allergies in general tend to be considerably underreported. allergic eye disease. In the discussion that follows, clinical, pathophysi- A survey conducted by the American College of Allergy, Asthma, and ological, and diagnostic aspects of each ocular process will be discussed Immunology (ACAAI) found that 35% of families interviewed experience in detail. These parameters are summarized in Tables 38.1 and 38.2. allergies. Of these individuals, at least 50% report associated eye symptoms. Fifty-five percent of allergic eye disease in Italy is SAC.1 Most reports Allergic Conjunctivitis: Seasonal or Perennial agree that allergic conjunctivitis affects up to 20% of the population.2 Introduction. Allergic conjunctivitis (AC) is a bilateral, self-limiting The distribution of SAC depends largely on the climate. For example, in conjunctival inflammatory process. It occurs in sensitized individuals (no the United States grass pollen–induced SAC generally occurs in the Gulf gender difference) and is initiated by allergen binding to IgE antibody Coast and southwestern areas of the country from March to October, on resident mast cells. The two forms of AC are defined by whether the and from May to August in most of the rest of the country. Conversely, inflammation and symptoms occur seasonally (spring, fall) or peren- ragweed pollen–induced SAC occurs in most of the country during August nially (year-round). Although the inflammatory signs and symptoms through October, but in the southern-most states it can begin as early are similar for both entities, seasonal allergic conjunctivitis (“hay fever as July and stretch out through November. Tree pollens can become a conjunctivitis”) is more common. It accounts for the majority of cases problem as early as January in the south, and March in the north. Race of AC and is related to pollens (e.g., grass, trees, ragweed) that appear and gender predilection follows that of rhinitis sufferers. during specific seasons. Perennial allergic conjunctivitis is often related to animal dander, dust mites, or other allergens that are present in the Pathogenesis and Etiology. It has been understood for some time environment year-round. Both SAC and PAC must be differentiated from that antigen cross-linking of immunoglobulin E (IgE) antibody bound the sight-threatening allergic diseases of the eye, namely AKC and VKC. to the high-affinity IgE receptor (FcεRI) on mast cells induces release of both preformed (granule associated, e.g., histamine and tryptase) Historical Perspective. Hypersensitivity reaction description of the and newly synthesized mediators (e.g., arachidonic acid metabolites), ocular surface dates to the earliest descriptions of hay fever or rhinitis. which have diverse and overlapping biologic effects. Both tissue staining Some of the earliest allergy provocation testing was performed in the and tear film data have implicated the mast cell and IgE-mediated conjunctiva. release of its mediators in the pathophysiology of the ocular allergic TABLE 38.1 Allergic Diseases of the Eye Disease Clinical Parameters Signs/Symptoms Differential Diagnosis Seasonal allergic conjunctivitis Sensitized individuals Ocular itching Infective conjunctivitis (SAC) Both females and males Tearing (watery discharge) Preservative toxicity Bilateral involvement Chemosis, redness Medicamentosa Seasonal allergens Often associated with rhinitis Dry eye Self-limiting Not sight threatening PAC/AKC/VKC Perennial allergic conjunctivitis Sensitized individuals Ocular itching Infective conjunctivitis (PAC) Both females and males Tearing (watery discharge) Preservative toxicity Bilateral involvement Chemosis, redness Medicamentosa Year-round allergens Often associated with rhinitis Dry eye Self-limiting Not sight threatening SAC/AKC/VKC Atopic keratoconjunctivitis Sensitized individuals Severe ocular itching Contact dermatitis (AKC) Peak incidence 20-50 years of age Red flaking periocular skin Infective conjunctivitis Both females and males Mucoid discharge, photophobia Blepharitis Bilateral involvement Corneal erosions Pemphigoid Seasonal/perennial allergens Scarring of conjunctiva VKC/SAC/PAC/GPC Atopic dermatitis Cataract (anterior subcapsular) Chronic symptoms Sight threatening Vernal keratoconjunctivitis Some sensitized individuals Severe ocular itching Infective conjunctivitis (VKC) Peak incidence 3-20 years of age Severe photophobia Blepharitis Males predominate 3 : 1 Thick, ropy discharge AKC/SAC/PAC/GPC Bilateral involvement Cobblestone papillae Warm, dry climate Corneal ulceration and scarring Seasonal/perennial allergens Sight threatening Chronic symptoms Giant papillary conjunctivitis Sensitization not necessary Mild ocular itching Infective conjunctivitis (GPC) Both females and males Mild mucoid discharge Preservative toxicity Bilateral involvement Giant papillae SAC/PAC/AKC/VKC Prosthetic exposure Contact lens intolerance Occurs anytime Foreign body sensation Chronic symptoms Protein buildup on contact lens Not sight threatening 608 SECTION D The Eye TABLE 38.2 Histopathologic and Laboratory Manifestations of Allergic Ocular Disease Disease Histopathology Laboratory Manifestations Seasonal/perennial allergic Mast cell/eosinophil infiltration in conjunctival epithelium and substantia Increased in tears: conjunctivitis propria Specific IgE antibody Mast cell activation Histamine Upregulation of ICAM-1 on epithelial cells Tryptase TNF-α Atopic keratoconjunctivitis Increased mast cells, eosinophils in conjunctival epithelium and Increased specific IgE antibody in tears substantia propria Depressed cell-mediated immunity Epithelial cell/goblet cell hypertrophy Increased IgE antibody and eosinophils in blood Increased CD4/CD8 ratio in conjunctival epithelium and substantia propria Eosinophils found in conjunctival scrapings Increased collagen Vernal keratoconjunctivitis Increased mast cells, eosinophils in conjunctival epithelium and Increased specific IgE/IgG antibody in tears substantia propria Elevated histamine and tryptase in tears Eosinophil major basic protein deposition in conjunctiva Reduced serum histaminase activity CD4+ clones from conjunctiva found to have helper function for local Increased serum levels of nerve growth factor and production of IgE antibody substance P Increased collagen Increased ICAM-1 on corneal epithelium Giant papillary conjunctivitis Giant papillae No increased histamine in tears Conjunctival thickening Increased tryptase in tears Mast cells in epithelium ICAM, intercellular adhesion molecule; Ig, immunoglobulin; TNF, tumor necrosis factor. inflammatory response. Additionally, a number of clinical studies exam- metabolites and tryptase originating from mast cells have also been ining topical antihistamine, mast cell stabilizing, and dual-acting drugs shown to be specifically involved in the regulation of many of these have demonstrated relief of allergic conjunctivitis symptoms (see same processes. Mast cells also synthesize cytokines and chemokines. Treatment). Less well documented and defined are the effects of these mediators in Histopathologic and laboratory manifestation of allergic ocular dis- the ocular allergic inflammatory process. Cytokines released by mast cells eases are shown in Table 38.2. Synthesis of inflammatory mediators contribute signals initiating infiltration of inflammatory white blood varies according to the phenotype and tissue location of the mast cell. cells, such as eosinophils. Once these cells arrive, they gain access to the Granule-associated neutral proteases (tryptase and chymase) unique conjunctival surface by moving through the already dilated capillaries. to mast cells are generally accepted as the most appropriate phenotypic Immunohistochemical staining of human conjunctival tissue biopsies markers to categorize human mast cells into subsets. Mast cells on shows that cytokines such as interleukin (IL-4), IL-5, IL-6, IL-13, and this basis have been divided into MCT (tryptase) and MCTC (tryptase/ tumor necrosis factor α (TNF-α) are localized to mast cells in both chymase) phenotypes.3 The phenotype of normal human conjunctival normal and AC specimens.12 Some of these cytokines (e.g., TNF-α) have mast cells has been well documented using immunostaining of con- also been detected in human tears of patients with AC.13–17 Although it junctival biopsy specimens. Mast cells are rarely present in the normal is difficult in vivo to determine the cellular source of cytokines in tears, human conjunctival epithelium, but when they are found, they appear recent studies comparing allergic to nonallergic subjects indicate that to be limited to the MCT phenotype. Mast cells (MCT phenotype) and cytokine levels may be important indicators of ocular allergy.16 It has eosinophils are increased in the conjunctival epithelium of individu- been demonstrated that tears from allergic donors (when compared with als with SAC and PAC (Table 38.2). Ninety-five percent of mast cells nonallergic donors) contained significantly less of the antiinflammatory in the substantia propria are MCTC; the total number of mast cells is cytokine IL-10 and a trend toward decreased levels of the Th1 cytokine, increased in AC.3–6 Clinical evidence for mast cell activation is found interferon γ(IFN-γ).16 Differences in biologic activity between allergic in SAC and PAC (Table 38.2). Tear film analysis of patients with AC and nonallergic tears have also been demonstrated in an in vitro bio- consistently reveals the presence of IgE antibody, histamine,7,8 trypt- assay using tears from allergic subjects to enhance eosinophil adhesion ase9 eotaxin,10 and eosinophil cationic protein.11 The contributions to conjunctival epithelial cells compared with tears from nonallergic of preformed (histamine, tryptase) and newly formed (leukotrienes, subjects.18 prostaglandins) mediators present in ocular inflammation have been Finally, IgE-mediated release of histamine and cytokines from mast well documented. Preformed mediators are released within seconds cells can initiate secondary effects on conjunctival epithelial cells. The to minutes upon allergen exposure, whereas hours are required for activation and participation of epithelial cells in allergic inflammation release of newly formed mediators, some of which may originate from is an active field of research. Human conjunctival epithelial cells express infiltrating cells like eosinophils. These mediators are known to have H1 receptors coupled to phosphatidylinositol turnover and calcium overlapping biologic effects that contribute to the characteristic ocular mobilization.19 Mast cell-mediated activation of conjunctival epithelial itching, redness, and watery discharge associated with allergic eye disease. cells has also been demonstrated in multiple in vitro studies in which Histamine is involved in the regulation of vascular permeability, smooth primary cultures of conjunctival epithelial cells were stimulated with muscle contraction, mucus secretion, inflammatory cell migration, cel- supernatants from IgE-activated conjunctival mast cells.20–22 These studies lular activation, and modulation of T cell function. Arachidonic acid demonstrated that TNF-α released from mast cells upregulates  CHAPTER 38 Allergic and Immunologic Diseases of the Eye 609 intercellular adhesion molecule 1 (ICAM-1) expression on conjunctival Treatment. Medications approved for use in allergic eye disease are epithelial cells.20 found in Table 38.3. Allergic conjunctivitis can be debilitating and may cause the individuals affected to seek any type of help for relief Clinical Features. The dominant symptom reported in allergic con- of symptoms. Itching and tearing may be unbearable and sleepless junctivitis is ocular itching (Table 38.1). Itching can range from mild nights frequent. Allergic conjunctivitis symptoms may be worse than to severe. Other symptoms include tearing (watery discharge), redness, the nasal symptoms in those suffering from rhinoconjunctivitis. Fur- swelling, burning, a sensation of fullness in the eyes or eyelids, an urge thermore, treatment of the nasal symptoms with topical nasal ster- to rub the eyes, sensitivity to light, and occasionally blurred vision. oids may help the rhinitis but not be as effective for relieving ocular As stated previously, allergic conjunctivitis is often associated with symptoms. symptoms of allergic rhinitis. Conjunctival hyperemia and chemosis Management of allergic conjunctivitis is, therefore, primarily aimed with palpebral edema are typical. Hyperemia is the result of vascular at preventing and alleviating symptoms. Some therapies may prevent dilation, whereas edema (chemosis) occurs because of altered perme- symptom development if used prior to the pollen season. The best ability of postcapillary venules. “Allergic shiners” (periorbital darkening), treatment is avoidance of the specific allergen, which, unfortunately, is caused by an increase of periorbital pigmentation resulting from the usually not possible. Avoidance of scratching or rubbing, application decreased venous return in the skin and subcutaneous tissue, are also of cool compresses, artificial tears, and refrigeration of topical ocular common. medications are practical interventions to alleviate discomfort. Although oral antihistamines may help to relieve eye itch, first generation drugs Patient Evaluation, Diagnosis, and Differential Diagnosis. An may also decrease tear production, causing more ocular symptoms. individual suspected of having allergic conjunctivitis should have a Topical medications are generally considered more effective to relieve thorough ocular, medical, and medication history. This will help greatly ocular itching than oral medications and may be additive to relief gained in differentiating AC from other ocular processes (Table 38.1). This from oral antihistamines. history should establish whether the process is acute, subacute, chronic, The treatment of choice for mild to moderate AC is a dual-acting or recurrent. It should further delineate whether the symptoms and topical ocular medication. The mast cell stabilizing component of these signs are unilateral or bilateral, and whether they are associated with drugs benefits patients most if treatment is started before the height any specific environmental or work-related exposure. Ocular symptoms of symptom onset. Patients usually note rapid onset of relief of itch such as tearing, irritation, stinging, and burning are nonspecific. A upon drop instillation, because most dual action medications have high history of significant ocular itching and a personal or family history of H1 receptor affinity. Drug dosing varies from one to four times per day, “hay fever,” allergic rhinitis, asthma, or atopic dermatitis are suggestive and efficacy is judged best by symptom relief. of ocular allergy. Because AC is secondary to environmental allergens In severe disease, combination therapy is recommended. This therapy as opposed to transmission by eye-hand contact (infectious etiology), may include topical medications (antihistamines, mast cell stabilizers, unless occurring in the context of petting an animal then rubbing one’s nonsteroidal antiinflammatory drugs [NSAIDs], or combinations), and eye, SAC and PAC usually present with bilateral symptoms. This is in oral antihistamines. Nonsteroidal drugs inhibit cyclooxygenase resulting contrast to transmissible infections caused by viruses and bacteria that in decreased formation of prostaglandins and thromboxanes, but not in general initially present in one eye, with the second eye becoming leukotrienes. Therefore these compounds are useful in controlling itching involved a few days later. Itch is an uncommon complaint during infec- and some inflammation but may not control the infiltration of inflam- tious conjunctivitis episodes. Furthermore, viral conjunctivitis may matory cells. In extreme cases, use of a low-potency topical steroid four cause subepithelial corneal infiltrates not seen in AC. Palpable pre- times a day should be considered. All patients receiving topical steroids auricular nodes would also signify infectious etiology for the ocular should have their intraocular pressure measured every 3 months and symptoms. be evaluated for cataract annually. There is no retrograde passage of The type of ocular discharge (watery, mucoid, or grossly purulent) nasal steroids up through the lacrimal sac, so any ocular effect is con- can also be helpful in determining the underlying cause of conjunctival sidered to be secondary to systemic absorption. A metaanalysis of grass inflammation. A watery discharge is most commonly associated with pollen allergen sublingual immunotherapy tablets for seasonal allergic viral or allergic ocular conditions. A mucoid or purulent discharge, rhinoconjunctivitis provides evidence of a small benefit.23 with morning crusting and difficulty opening the eyelids, would strongly suggest a bacterial infection. Atopic Keratoconjunctivitis In allergic inflammation, the eye appears red. Vision, pupil shape, Historical Perspective. AKC is a bilateral, chronic inflammation of ocular movement, light reactivity, and the red retinal reflex remain the conjunctiva and lids associated with atopic dermatitis. Hogan, in normal in allergic conjunctivitis. Dry eye (secondary to a decrease of 1953, was the first to describe the findings of chronic conjunctivitis the aqueous portion of the tear film) gives symptoms suggestive of and keratitis in patients with atopic dermatitis.24 Between 3% and 17% foreign body in the eye and may result in conjunctival redness. Similar of the population has atopic dermatitis.25,26 From 15% to 76% of patients symptoms are possible from anticholinergic side effects of systemic with atopic dermatitis have ocular involvement, usually AKC.25,27,28 medications. Typically, itch is not reported with dry eye. Medication history should include questions concerning the patient’s Epidemiology. The onset of disease is usually in the second through use of over-the-counter topical ocular medications, cosmetics, contact fifth decade, although the majority of patients with atopic dermatitis lenses, and systemic medications. Any of these can produce acute or are diagnosed by age 5 years. Series report the onset of symptoms chronic conjunctivitis. This inquiry should include direct questions between the ages of 7 and 76 years.29–31 The highest male to female ratio and should not rely on the patient to volunteer information. Many is reported as 2.4 : 1.29,31 No racial or geographic predilection is reported. individuals do not appreciate the potential for nonprescription topical Seven percent of 3545 patients with allergic eye disease in Italy were ocular medications to cause eye symptoms or partially treat AC. Dif- classified as having AKC.32 ferentiation of AC from the more chronic and sight-threatening forms of allergic eye disease is discussed later in the context of the specific Pathogenesis and Etiology. Atopic keratoconjunctivitis is thought conditions. to consist of both type 1 and type 4 hypersensitivity mechanisms. 610 SECTION D The Eye TABLE 38.3 Topical Treatments and Activity of Compounds Drug and Inhibition of Mediator Release From Classification Human Conjunctival Mast Cells Inhibitory Effects on Other Cells References Antazoline No effect Inhibits IL-6, IL-8 release from conjunctival epithelial 169,170 H1 receptor antagonist cells in vitro Pheniramine No effect Inhibits IL-6, IL-8 release from conjunctival epithelial 169,170 H1 receptor antagonist cells in vitro Emedastine No effect Inhibits IL-6, IL-8 release from conjunctival epithelial 169,170 H1 receptor antagonist cells in vitro Levocabastine No effect Inhibits IL-6, IL-8 release, ICAM-1 expression on 169,170 H1 receptor antagonist conjunctival epithelial cells in vitro Olopatadine Histamine, tryptase, PGD2, TNF-α in vitro Conjunctival mast cell TNFα-mediated upregulation of 169,170 H1 receptor antagonist ICAM-1 on conjunctival epithelial cells in vitro Mast cell stabilizer Ketotifen Histamine in vitro Chemotaxis and activation of eosinophils in vitro 169,170 H1 receptor antagonist Mast cell stabilizer Azelastine In vitro data not available Activation of eosinophils in vitro 169,170 H1 receptor antagonist Eosinophils and neutrophils in tears Mast cell stabilizer ICAM-1 expression in vivo Cromolyn Not inhibitory for histamine release in vitro Chemotaxis and activation of eosinophils, neutrophils, 169,170 Mast cell stabilizer Tryptase in tears monocytes in vitro Lodoxamide In vitro data not available Chemotaxis and activation of eosinophils in vitro 169,170 Mast cell stabilizer Histamine and tryptase in tears Eosinophils, neutrophils, T cells in tears ICAM-1 expression on conjunctival epithelial cells in vitro Nedocromil Not inhibitory for histamine release in vitro IgE synthesis from B cells 169,170 Mast cell stabilizer ICAM-1 and HLA-DR expression on conjunctival epithelial cells in vitro Activation and survival of eosinophils in vitro Pemirolast Not inhibitory for histamine release in vitro Activation of eosinophils and neutrophils in vitro 169,170 Mast cell stabilizer Alcaftadine Histamine in vitro Chemotaxis and activation of eosinophils 171 H1 receptor antagonist Mast cell stabilizer Bepotastine Histamine in vitro Chemotaxis of eosinophils in vitro 172 Mast cell stabilizer ICAM, Intercellular adhesion molecule; Ig, immunoglobulin; IL, interleukin; TNF, tumor necrosis factor. Evidence of the pathologic process comes from histologic and immu- have protease activity.39 Anti–thymic stromal lymphopoietin (TSLP) nohistochemical analysis of conjunctival biopsy specimens and from immunohistochemical staining showed preferential expression in the tear fluid analysis for mediators and cells. The skin and conjunctiva epithelial cells of giant papillae in AKC.40 are more likely to be colonized with enterotoxin-producing Staphylococ- The substantia propria in AKC has an increased number of mast cus aureus bacteria than normal.33 cells compared with normal. Conjunctival inflammatory cell density Mast cells and eosinophils are found in the conjunctival epithelium showed a negative correlation with tear stability and corneal sensitivity of AKC patients but not in normal individuals.6 Mast cells in the epi- and a positive correlation with the vital staining scores.41 Eosinophils, thelium of AKC patients contain predominantly tryptase as the neutral rarely found in normal structures, are present in the substantia propria protease.34 This suggests an upregulation of antigen presentation. There in AKC. These eosinophils are found to have increased numbers of is an increase in the CD4:CD8 ratio in AKC over normal conjunctival activation markers on their surface.42 A large number of mononuclear epithelium.35 This increase of CD4 or helper T cells probably serves to cells are present in the substantia propria. Fibroblast number is increased, amplify the immune response that is occurring. In vivo confocal and there is an increased amount of collagen compared with normal microscopy reveals fewer basal epithelial cells in the cornea.36 Mucin individuals. In addition, the substantia propria demonstrates increased proteins and mRNA are increased in the epithelium.37,38 Conjunctiva CD4/CD8, B cells, human leukocyte antigen (HLA)-DR staining, and epithelial protease activated receptor (PAR-2) exposed to innate secre- Langerhans cells.35 The T cell population of the substantia propria tory leukocyte protease inhibitor (SLPI) show reduced release of IL-6 includes CD4 and memory cells.43,44 Th2 cytokines predominate in and IL-8. Any imbalance of the protease inhibitors may lead to increased allergic disease, yet lymphocytes with Th1 cytokines have been found amounts of IL-6 and IL-8 from exposure to mite allergen, known to in the substantia propria of AKC patients.43  CHAPTER 38 Allergic and Immunologic Diseases of the Eye 611 AKC has reduced tear break-up time indicating poor function of same surface problems but has been shown to improve vision in some.49 meibomian gland oils and decreased Schirmer values (56% less than Herpes simplex keratitis is reported to occur in 14% to 17.8% of 5 mm), compared with controls.38,45 Tabbara et al. report development patients.29,31 Keratoconus, a noninflammatory progressive thinning of of AKC in bone marrow recipients whose donors had a history of VKC the cornea, occurs in 6.7% to 16.2% of patients.29,31 or atopic dermatitis.46 Messmer and colleagues showed eosinophils and Anterior uveitis and iris abnormalities are not reported. The preva- their products deposited in the ulcers and stroma of corneas from AKC lence of cataract associated with AKC is probably increased, because patients.47 steroids are so frequently used in the treatment of the disease. The lens In summary, AKC patients demonstrate an increased number of opacity typically associated with AKC, however, is an anterior or sub- conjunctival mast cells and evidence of mast cell and eosinophil activa- capsular cataract. This cataract often has the configuration of a multi- tion. Furthermore, a complex immune cell profile implicates more than lobed opacity resembling a “milk splash.” Retinal detachment with or these mast cells alone, but the details of the initiation and perpetuation without previous cataract surgery is the principal posterior manifestation of these cellular responses remains unclear. of AKC reported.50–52 Clinical Features. Itching is the major symptom of AKC. This may Patient Evaluation, Diagnosis, and Differential Diagnosis. Para- be more pronounced in certain seasons or it may be perennial. Other mount to both diagnosis and treatment in AKC is a careful history. The symptoms, in decreasing order of frequency, include watering, mucous patient typically describes severe, persistent, periocular itching associated discharge, redness, blurring of vision, photophobia, and pain.31 Exac- with dermatitis. There is usually a family history of atopic disease in erbation of symptoms most frequently occurs in the presence of fur- one or both parents and commonly other atopic manifestations in the bearing animals and pets.31 Signs of AKC include skin, lid margin, patient, such as asthma (65%) or allergic rhinitis (65%).30 A history of conjunctival, corneal, and lens changes (Table 38.2). The periocular seasonal or exposure-related exacerbations is usually present. History skin often shows a scaling, flaking dermatitis with a reddened base (Fig. and examination reveal features to help differentiate AKC from other 38.3). The skin of the lids may become leather-like, developing cicatricial atopic ocular conditions. The lack of contact lens wear aids in differ- ectropion (turning outward of the lid from skin scarring) and lagoph- entiating AKC from GPC. AKC patients are usually older and have thalmos (incomplete closure of eyelids). Lateral canthal ulceration and major lid skin involvement compared with patients with VKC. SAC cracking as well as lash loss (madarosis) may also be present. This may patients have no or markedly diminished symptoms out of their season be the principal manifestation in a minority of cases. The lid margins and show no evidence of chronic inflammation in the conjunctiva. The may show meibomitis, keratinization, and punctal ectropion. The con- significant past history or concurrent presence of eczema cannot be junctiva of the tarsal surfaces can manifest a papillary reaction and emphasized enough as a finding in patients with AKC. The serum level possibly pale white edema. In contrast to VKC, the papillary hypertrophy of IgE is often elevated in patients with AKC. Transepithelial leakage of AKC is more prominent in the inferior conjunctival fornix. Subepi- of fluorescein and extravascular interstitial accumulation of ICG may thelial fibrosis is present in many, fornix foreshortening in some, and be useful markers of disease activity patients in AKC.53 CCL24 (eotaxin-2) symblepharon (scar of conjunctival surface of lid to conjunctiva of the mRNA expression levels on the ocular surface are a useful biomarker globe) in a few. The bulbar conjunctiva may have few findings besides for clinical severity of AKC.54 erythema and chemosis. A perilimbal, gelatinous hyperplasia may occur. Horner-Trantas dots (whitish dots that are aggregates of degenerated Treatment. The approach to treatment is multifaceted and includes epithelial and eosinophils that accumulate at the surface of the hyper- environmental controls as well as topical and systemic medications. It plastic, gelatinous limbus) have been reported to occur in AKC.48 is unlikely that the AKC patient will see the ophthalmologist without Significant vision loss in this disease usually results from pathologic also being under the care of a primary care physician and allergist. conditions of the cornea. Punctate epithelial keratopathy is the most However, the patient must remove environmental irritants in both the common corneal finding. Persistent epithelial defects, scarring, microbial home and the employment or school setting. The nature of the irritants ulceration, and neovascularization are the main corneal causes for may be better defined through allergy testing. decreased vision (Table 38.2). Penetrating keratoplasty is at risk of the The topical application of a vasoconstrictor-antihistamine combi- nation may bring transient relief of symptoms but is unlikely to alter the immunopathologic process or its sequelae. There is potential for overuse because of the chronic nature of the disease. The potent topical antihistamines offer much greater H1 receptor antagonism than over- the-counter antihistamines. The topical administration of steroids such as prednisolone acetate eight times per day for 7 to 10 days is clearly beneficial in controlling symptoms and signs. These agents, of course, must be used judiciously, because the chronic nature of the disease may encourage overuse. The patient must be instructed that steroid use must be transient only and must be carefully monitored for efficacy as well as warned of the potential for causing cataract and glaucoma. Nonsteroid medications have been shown to be effective in reducing itching, tearing, and photophobia. Topical mast cell stabilizers one to four times daily are recommended year-round in patients with perennial symptoms. If an exacerbation occurs and the patient is not taking a mast cell stabiliz- ing agent topically, its use should be initiated one to four times daily concurrent with a short burst of topical steroids (for 7 to 10 days). Mast cell stabilizers alone such as cromolyn, nedocromil, lodoxamide, Fig. 38.3 Atopic keratoconjunctivitis. Periocular skin involvement of or mast cell stabilizer antihistamine combinations such as olopatadine, atopic dermatitis. azelastine, epinastine, and ketotifen, may be helpful. Cyclosporine-A 612 SECTION D The Eye and tacrolimus, both orally and topically have been shown effective at and mononuclear cells in the hyperplastic epithelium.70 Brush cytology treating AKC as well as reducing the amount of topical steroid use.55–60 of the conjunctival epithelium from patients with VKC showed more Tear levels of eosinophilic cationic protein are reduced following treat- eosinophils and neutrophils in patients with corneal erosion or ulcer ment with topical tacrolimus.61 The level of IL-8, eosinophil cationic than in those without.72 Goblet cell density is not elevated in the con- protein (ECP), and total IgE in the tears of AKC patients was reduced junctival epithelium of VKC.73 Some neurotransmitters, their receptors, significantly 4 to 6 weeks after the start of rebamipide treatment.62 integrins, growth factors, toll-like receptor 2, CCL20/MIP-3 alpha mRNA, Foster and Calonge recommend maximizing the use of systemic and the inflammation modulating peptide thymosin-beta 4 are found antihistamines.29 Only in rare cases of uncontrolled dermatitis with in greater amount in VKC epithelium compared with normal epithe- vision-threatening complications are oral steroids indicated. Plasma- lium.74–77 Eosinophil major basic protein is deposited diffusely throughout pheresis has been effective in the treatment of AKC.63 the conjunctiva of VKC patients, including the epithelium.78 Cornea Lid and ocular surface abnormalities may require treatment other and conjunctiva in vivo confocal microscopy confirm much of the than that directed toward the underlying pathologic condition of AKC. histology that is described and offers an additional diagnostic aid in Trichiasis or lid position abnormalities, if contributing in any way to uncertain cases.79,80 corneal compromise, must be corrected. The ocular surface inflamma- The substantia propria contains elevated numbers of mast cells tion, lid malposition, and lid margin keratinization may contribute to compared with normal individuals.69,70 The predominant mast cell the development of limbal stem cell deficiency. Three percent of limbal subtype is again MCTC. Forty-six percent of the mast cells in the sub- stem cell transplants are performed for stem cell deficiency from AKC.64 stantia propria contain fibroblast growth factor (β-FGF).81 This may Any staphylococcal blepharitis should receive adequate antibiotic treat- serve as a stimulus for fibroblast growth and production of collagens. ment. If, despite adequate control of signs and symptoms of AKC, corneal Eosinophil major basic protein deposition is found close to mast cells in punctate staining persists, artificial tears should be used to aid in avoid- VKC.78 As in the epithelium, the substantia propria contains increased ing the development of corneal epithelial defects. It may be extremely numbers of eosinophils and basophils compared with normal tissue.69 difficult to achieve reepithelization in these defects, and surgical A unique profile of lymphocytes is found. T cells can be isolated from approaches have been attempted. Lid or ocular surface herpes simplex biopsy specimens of VKC tarsal conjunctiva. These CD4+ T cells show virus (HSV) infection should be treated with oral and topical antiviral helper function for IgE synthesis in vitro and produce IL-4.82 This agents. Care should be taken in using these to achieve viral eradication would support the notion that IgE is produced locally. Calder et al., without sustained use and subsequent epithelial toxicity. If frequent in separate work, found IL-5 expressed in T cell lines generated from recurrent episodes of epithelial HSV keratitis occur, one may consider VKC biopsy specimens.83 The substantia propria stains positive for oral acyclovir (400 mg orally twice daily) as prophylaxis against metalloprotease 9, epidermal growth factor receptor (EGFR), trans- recurrences. forming growth factor β (TGF-β), β-FGF, platelet-derived growth factor (PDGF), and thymosin-β4 associated with inflammatory cells.75,76,84 The Vernal Keratoconjunctivitis substantia propria also has an increased amount of collagen. Fibro- Historical Perspective. Vernal keratoconjunctivitis (VKC) is a chronic, blasts from the tarsal conjunctival biopsy of VKC patients can be bilateral conjunctival inflammatory condition found in individuals induced to proliferate by histamine and epithelium-derived growth predisposed by their atopic background. An excellent review of the factor.70 history and description of this disease was published by Kumar in The corneal epithelium of VKC patients has been shown to express 2008.65 Beigelman’s 1950 monograph Vernal Conjunctivitis continues ICAM-1, an important cell adhesion molecule.85 Eosinophil peroxidase, to be the most exhaustive compilation on this disease and is unmatched.66 in contact with human corneal epithelial cells, causes disruption of cell adhesion.86 Eosinophil major basic protein and eosinophil cationic protein Epidemiology. The onset of disease is generally before age 10 years are proinflammatory and have been shown to be cytotoxic to corneal and lasts 2 to 10 years, usually resolving during late puberty. Only 11% epithelium.87 In vitro, both of these damage the monolayers of human of patients were older than 20 years of age in the Bonini series.67 Males corneal epithelial cells but not the stratified corneal epithelial cells in predominate in the younger ages, but the male to female ratio is nearly culture. Confocal microscopy demonstrates a significant reduction in equal in older age patients. Young males in dry, hot climates are primar- number of dendritic cells in the subbasal epithelium of VKC patients ily affected. The Mediterranean and West Africa are areas with the following treatment for 3 to 6 months.88 Earlier studies by confocal greatest prevalence. Nine percent of 3545 patients with allergic eye microscopy demonstrate lower density of keratocytes, increased presence disease in Italy were classified as having VKC: 22% of those 18 years of activated keratocytes, and inflammatory cells in the anterior stroma or younger in the series had VKC.32 VKC is relatively unusual in most and higher grade of tortuosity of fibers in the subbasal nerve plexus.80 of North America and Western Europe. There is a significant history Allergen-specific IgE and IgG have been isolated from the tears of of other atopic manifestations, such as eczema or asthma, in 40% to VKC patients.89,90 Histamine, tryptase, hemopexin, transferrin, and 75% of patients with VKC.68 A family history of atopy is found in 40% sIL-6R are elevated in the tears of VKC patients.7,9,91,92 The serum of to 60% of patients.67 Seasonal exacerbation, as the name implies, is VKC patients has been found to contain decreased levels of histaminase, common, but patients may have symptoms year-round. vitamin D, sex hormones (dependent on the phase of disease), and increased levels of nerve growth factor.93–96 Finally, VKC is reported to Pathogenesis and Etiology. Biopsy of a tarsal conjunctival papilla occur in patients with the hyperimmunoglobulin E syndrome.97 in VKC reveals distinct findings. The epithelium contains large numbers of mast cells and eosinophils, neither of which are found in normal Clinical Features. Severe itching and photophobia are the main individuals.69,70 Human mast cells may be categorized based on the symptoms. Associated foreign body sensation, ptosis, thick mucous presence of neutral proteases.3 The epithelium of VKC patients contains discharge, and blepharospasm occur. The signs are confined mostly to mast cells predominantly of the type containing the neutral proteases the conjunctiva and cornea; the skin of the lids and lid margin are tryptase and chymase (MCTC).71 Basophils are found in the epithelium relatively uninvolved compared with AKC. The conjunctiva develops a and may indicate that one form of a delayed-type hypersensitivity reac- papillary response, principally of the limbus or upper tarsus. The tarsal tion is occurring. Leonardi et al. demonstrated eosinophils, neutrophils, papillae are discrete, greater than 1 mm in diameter, have flattened tops  CHAPTER 38 Allergic and Immunologic Diseases of the Eye 613 that may stain with fluorescein, and occur more frequently in European is not.98 Recently, subcutaneous immunotherapy did result in significant and North American patients.98 Thick, ropy mucus tends to be associ- reduction in symptoms and serum IgE compared with topically treated ated with the tarsal papilla (Fig. 38.4). These are the classic “cobblestone” patients.103 papillae. For the patient with a significant seasonal exacerbation, a short-term, Limbal papillae tend to be gelatinous and confluent, and they occur high-dose pulse regimen of topical steroids is necessary. Usually, dexa- more commonly in African and West Indian patients.99 Horner-Trantas methasone 0.1%, prednisolone phosphate 1%, or 0.05% difluprednate dots, which are collections of epithelial cells and eosinophils, may be eight times daily for 1 week brings excellent relief of symptoms. The found at any meridian around the limbus.100 These changes may lead topical steroids should be tapered to as little as is needed both in fre- to superficial corneal neovascularization. The forniceal conjunctiva quency and potency to maintain patient comfort but avoid steroid- usually does not show foreshortening or symblepharon formation. associated complications such as cataract and elevated intraocular The corneal findings may be sight threatening. Buckley describes in pressure. As in any chronic ocular inflammation, use of steroids should detail the sequence of occurrence of corneal findings.98 Mediators from be limited and steroid alternatives introduced rapidly once symptoms the inflamed tarsal conjunctiva cause a punctate epithelial keratitis. controlled. Cromolyn sodium, a mast cell stabilizer, has repeatedly been Coalescence of these areas leads to frank epithelial erosion, leaving shown to be effective in VKC.104–106 At the time of an exacerbation, the Bowman’s membrane intact. If, at this point, inadequate or no treatment patient should be given a steroid pulse dose and begin using a mast is rendered, a plaque containing fibrin and mucus deposits over the cell stabilizing drug topically or a dual-acting drug such as olopatadine, epithelial defect.101 Epithelial healing is then impaired, and new vessel ketotifen, epinastine, or azelastine concurrently to provide mast cell growth is encouraged. This so-called shield ulcer usually has its lower stabilization and antihistamine treatment. Oral medications that have border in the upper half of the visual axis. With resolution, the ulcer- a variable role include steroids, antihistamines, and nonsteroidal anti- ated area leaves a subepithelial ring-like scar. The peripheral cornea may inflammatory agents.7,107 For the care of severe bilateral vision-threatening show a waxing and waning, superficial stromal, gray-white deposition disease, oral steroids may be used, but using this treatment for VKC termed pseudogerontoxon. Iritis does not occur in VKC. alone is unusual. Maximizing the use of nonsedating antihistamines is often helpful. Patient Evaluation, Diagnosis, and Differential Diagnosis. The Topical calcineurin inhibitors of cyclosporine A (CsA) and tacrolimus diagnosis is based on the history and physical findings. As indicated have been demonstrated to be effective in the treatment of VKC.108,109 previously, VKC occurs predominantly in young boys living in warm An open pilot study of the use of Lactobacillus acidophilus probiotic eye climates. These patients have intense photophobia, ptosis, and the char- drops in patients with VKC significantly reduced signs and symptoms in acteristic finding of giant papillae. The principal differential diagnostic patients.110 Phototherapeutic keratectomy and keratectomy with amni- entity is AKC. The two are compared and contrasted in Table 38.1. Tear otic membrane graft placement have been shown to be effective.111,112 fluid analysis and cytology, conjunctival scraping for cytology, and biopsy Climatotherapy may be beneficial. This form of therapy may involve are rarely needed to assist in establishing the diagnosis. A distinctive simple measures, such as cool compresses over the closed lids. Main- “protein tear print” is found to predict VKC activity.102 tenance of an air-conditioned environment or relocation to a cool, dry climate is most helpful during seasonal exacerbations. However, the Treatment. As with any atopic condition, avoidance of allergens is economic and geographic restrictions of these measures are obvious. important, although many afflicted are skin test negative. Patients who Cryoablation of upper tarsal cobblestones is reported to render are skin test positive to multiple allergens will find avoidance difficult. short-term improvement. However, scar formation from this may lead Seasonal removal of affected children from their home to a reduced to lid and tear film abnormalities. The risk of these adverse permanent allergen climate is usually not practical for most families. What is practi- changes is probably not warranted in this usually self-limited disease. 98 cal and should not be overlooked is alternate occlusive therapy as an Surgical removal of the upper tarsal papilla in combination with for- allergen avoidance strategy. Allergen immunotherapy in VKC has limita- niceal conjunctival advancement or buccal mucosal grafting may result tions. It is not feasible to desensitize these children to all of the allergens in obliteration of the fornix.66,113 Injection of short- or long-acting to which they are responsive. Moreover, some suggest that while skin steroids into the tarsal papilla has been shown to be effective at reducing and lung symptoms are responsive to immunotherapy, the conjunctiva their size.114,115 Excision of upper tarsal papillae with or without adjunc- tive use of mitomycin-C or application of amniotic membrane is reported to be helpful.116–118 Subcutaneous administration of omalizumab resulted in clinical improvement in some VKC patients.119,120 Serum levels of α-1 antitrypsin, high-mobility group box protein 1 (HGMB1), and receptor for advanced glycation end products (RAGE) are reduced with topical treatment of VKC patients and may serve as a marker of efficacy of treatments.121,122 The therapy of the future will be directed toward diminishing mast cell numbers or function and immunomodulation of the cell-mediated response. Giant Papillary Conjunctivitis Introduction. Giant papillary conjunctivitis (GPC) is a chronic inflam- matory process leading to the production of giant papillae on the tarsal conjunctiva lining of the upper eyelids. Historical Perspective. Most often associated with soft contact lens wear, GPC has been reported in patients wearing soft, hard, and rigid Fig. 38.4 Cobblestone papillae of the upper lid conjunctiva in vernal gas-permeable contact lenses, as well as in patients with ocular prostheses keratoconjunctivitis. and exposed sutures in contact with the conjunctiva. 614 SECTION D The Eye Epidemiology. GPC may affect as many as 20% of soft contact lens wearers.123 Those people wearing regular (as opposed to disposable) soft contact lenses are at least ten times more susceptible to GPC than rigid (gas-permeable) contact lens wearers. Those patients using daily- wear disposable contact lenses and those wearing rigid contact lenses are about equally affected. Patients who wear disposable contact lenses during sleep are probably three times more likely to have GPC symptoms than if the lenses are removed daily. Patients with asthma, SAR, or animal dander allergies may be at greater risk for GPC.124 There are no gender or race predilections reported. Pathogenesis and Etiology. The onset of GPC may be the result of mechanical trauma secondary to contact lens fit or a lens edge causing chronic irritation of the upper eyelid with each blink. It is more likely, however, that a buildup of “protein” on the surface of the contact lens causes an allergic reaction in the eyelid tissue.125 Tear clearance from the ocular surface of GPC patients is decreased compared with unaf- fected eyes, and this may allow the protein in the tear film longer contact time with the contact lens.126 As with AKC and VKC, tissue biopsies are the primary source of data on the pathophysiology of this GPC. Table 38.2 summarizes these findings. Many of the published studies concern- Fig. 38.5 Giant papillae associated with soft contact lens wear. ing mast cell involvement in GPC contrast the disease with VKC. Like VKC, conjunctival biopsies in GPC are found to have mast cells of the MCT type in the conjunctival epithelium.34 However, there is no sig- nificant increase in mast cells in the substantia propria, and thus no opacification as inflammatory cells enter the tissue. Eventually, the overall increases in number of mast cells present in the conjunctival recurrent irritation is so great as to cause the enlarged papillae that will tissue. Interestingly, although increased histamine is measured in tears be the source of increased mucous and inflammatory mediators and in patients with VKC, patients with GPC have normal tear histamine decrease in wear time. The differential diagnosis includes VKC that levels.7,123 This can be partially explained from electron microscopy occurs in young boys not wearing contact lenses. data on biopsies from patients with GPC, which has revealed less mast cell degranulation (30%) than is observed in patients with VKC (80%).127 Treatment. Reducing symptoms is the primary aim for management Tryptase has also been found in the tears from patients with GPC. This of GPC. A reduction in the wearing time of contacts from a few hours is not surprising considering the fact that rubbing alone can result in a day to total abstinence may be required. Once a day use contact lenses significant increases of tryptase in tears.9 Eotaxin is not found to be may be a consideration for persistent cases of GPC. However, in more elevated in the tears of GPC patients, even though eosinophils are serious cases, a more aggressive approach may be required to prevent increased in tissues.128 As in SAC and PAC, release of mediators from ocular tissue damage. This usually entails a complete holiday from lens mast cells results in increased capillary permeability and inflammatory wear in conjunction with a topically applied antiinflammatory drug. cell infiltration of eyelid tissue. Cytologic scrapings from the conjunctiva Topical mast cell stabilizers have been shown to be effective in the of patients with GPC exhibit an infiltrate containing lymphocytes, plasma treatment of GPC.129–132 Combination drugs with mast cell stabilizing cells, mast cells, eosinophils, and basophils. All of these factors contribute as well as antihistamine activity may relieve the itch and decrease the to discomfort and formation of the papillae. The differentiating patho- inflammation. A patient with GPC may require continued use of these physiologic characteristics between GPC and VKC are important, because drugs once they return to contact lens wear. Steroids have also been they could be considered as possible clues to the differences in patho- approved for the treatment of GPC.133 Topical steroids and tacrolimus genesis between these two ocular diseases. are demonstrated to be effective in treating GPC.134,135 A return to contact lens wear can usually be accomplished but may require a change in Clinical Features. Symptoms of GPC include ocular itching after contact lens style or lens material. lens removal, redness, burning, increased mucous discharge in the morning, photophobia and decreased contact lens tolerance (Fig. 38.5). Blurred vision can result from deposits on the contact lens or from CONJUNCTIVAL PROVOCATION TESTING displacement of the contact lens secondary to the superior eyelid papil- The conjunctival provocation test (CPT) has traditionally been used lary hypertrophy. Initial presentation may occur months or even years as a means for diagnosing ocular allergy. A discussion of CPT is impor- after the patient has begun wearing contact lenses. tant in this chapter, because it is currently used routinely as a human model system to study allergic conjunctivitis and drug efficacy. Although Patient Evaluation, Diagnosis, and Differential Diagnosis. In evaluation of subjects during allergy season is still a valid and important mild cases of GPC, small papillae may occur. These papillae are thought approach to the study of allergic conjunctivitis, variations in exposure to be caused by the contact lens riding high on the surface of the eye to allergens (based on environment and lifestyle) and compliance issues with each blink. In very mild cases this tendency of the contact lens to are serious impediments to collecting statistically relevant data. ride up on the eye may contribute to the diagnosis in the absence of The currently most widely accepted model protocol for CPT was visible papillae. In cases of chronic GPC, tear deficiency may be a con- developed by Abelson and coworkers.136 This protocol allows researchers tributing factor. Redness of the upper eyelid on ocular examination is to examine the ocular response to allergen in a controlled setting. Before one of the earliest signs of GPC, and this observation can facilitate early undertaking a CPT study, subjects must first be skin tested with com- diagnosis. Abnormal thickening of the conjunctiva may progress to mercial allergen extracts to determine the appropriate allergen and  CHAPTER 38 Allergic and Immunologic Diseases of the Eye 615 concentration for each subject. It is very important to conduct CPT CONTACT DERMATITIS out of season for the allergen of interest and to observe published local pollen counts to ensure that no environmental exposure occurs during Introduction the course of the study. In the study design, two baseline visits (7 days Contact dermatitis is a delayed inflammatory hypersensitivity reaction apart) are used to establish the threshold dose of allergen. At the first resulting from contact with a specific antigen or irritant (Chapter 34). baseline visit, increasing doses of allergen extract are applied bilaterally Although not an IgE antibody–mediated process, it deserves discussion into the conjunctival sac of the eye at 10-minute intervals followed by in this chapter, because contact dermatoconjunctivitis is a commonly observation for hyperemia, itching, chemosis, and lid swelling according observed entity in the ocular adnexa. The eye is affected in this disorder to well-established scales, as shown in Table 38.4. A threshold of reac- not only via direct application of substances containing irritants (often tivity of 2+ is considered to reflect the severity of allergic conjunctivitis ophthalmic treatments) and specific antigens, but also through eye in season. rubbing following manual contact with an offending irritant or antigen. A second baseline (7 days later) visit is necessary to establish repro- Because the potential list of substances causing contact dermatitis ducibility of the ocular allergic reaction to the threshold dose of allergen numbers in the thousands, it is one of the most common skin condi- extract. The CPT protocol consists of a double-blind, randomized design tions requiring medical attention. in which the test drug is applied to one eye and placebo to the other. After 10 minutes, the subject is challenged with the previously deter- Epidemiology mined threshold dose of allergen extract. Symptom evaluation is then It is unclear exactly how many people suffer from the ocular component conducted according to standardized scales and at various time points of this process, but the recent international workshop estimate for the post-challenge (approximately 20 minutes for immediate and up to 6 incidence of contact dermatitis, in general, ranges from 15% to 20% hours for late reactions). Subsequent visits may be used to examine of the general population in Western industrial nations.145 other parameters of interest, such as prophylactic potential of the test drug or duration of drug efficacy in response to later time-points of Pathogenesis allergen challenge. The therapeutic effect of a drug can also be evaluated This is reviewed in detail in Chapter 34. by performing CPT after drug exposure. Safety of the procedure is supported by the lack of anaphylaxis in children undergoing CPT for Clinical Features peanut allergy compared with oral food challenge.137 Symptoms and signs of contact dermatoconjunctivitis can include a Application of the guidelines put forth in the Abelson model for sudden rash over the eyelids, tearing, redness, itching, stinging and CPT has improved the reproducibility and objectivity of topical drug burning sensations, and a sensation of fullness in the eye or eyelid when efficacy evaluation in human trials. Important advantages include stan- swelling is involved (Fig. 38.6). The eyelid may appear thickened, red, dardization and confirmation of the threshold dose, use of a standardized and sometimes ulcerated. When the conjunctiva is involved, vasodilation, scale for symptom scores, and comparison of the treated eye to the chemosis, watery discharge, and sometimes formation of papillae can contralateral untreated eye as an internal control. Digital analysis of be observed. Chronic inflammation may involve occlusion of lacrimal redness of the eye has been developed to aid in assessing CPT.138 ducts, conjunctival scarring, corneal neovascularization and keratiniza- In conjunction with the clinical parameters evaluated in the CPT tion, but sight loss is uncommon. model, many researchers have also been able to analyze tear fluid obtained A multitude of irritants and antigens has been implicated in ocular with the CPT procedure to determine mediators and cell types contact dermatitis. Some common substances known to sensitize indi- present.139,140 It has been shown that conjunctival allergen provocation viduals to ocular contact dermatitis include topical drugs and antibiotics in atopic subjects results in release of mediators in tears known to come (anesthetics, neomycin, antivirals, pilocarpine, and timolol), preserva- from mast cells, such as histamine, tryptase, prostaglandins, and leu- tives in ophthalmic solutions (thimerosal, benzalkonium chloride, kotrienes C4 and D4.141–143 Additionally, it has been shown that two chlorobutanol, chlorhexidine, and ethylenediaminetetraacetic acid histamine peaks (20 minutes and 6 hours) follow allergen provocation, [EDTA]), cosmetics (eye and lip glosses containing waxes, fats, and not unlike what is seen during the acute and late phase responses in dyes), perfumes, sunscreens containing para amino benzoic acid (PABA), the skin and airways. Since only an early tryptase peak is measured, fingernail products (containing formaldehyde resins and sulfonamide this may indicate either the involvement of basophils in the late phase derivatives), hair products (dyes and permanent solutions), adhesives or, possibly, refractory mast cells.144 Recent techniques facilitating analysis (false eyelashes), nickel (eyelash curlers and eyeglass frames), irritant of cytokines in tears could also be combined with the CPT model to plants (poison ivy, sumac, and oak), and latex (gloves). Examples of better understand both the mechanisms of action of ocular drugs and other irritant substances implicated in contact dermatoconjunctivitis the pathophysiology of allergic conjunctivitis.16 include soaps, detergents, bleach, and solvents. TABLE 38.4 Grading Scales for Symptom Scores in Conjunctival Provocation Testing Score Itching Hyperemia Chemosis Lid Swelling 0.0 None None None None 1.0 Intermittent tickling sensation Mild: dilated blood vessels Mild: confirmed with slit-lamp Mild: detectable swelling of lower lid evaluation 2.0 Mild continuous ocular itching Moderate: dilation of blood vessels Moderate: raised conjunctiva Moderate: definite swelling of lower lid 3.0 Severe ocular itching Severe: numerous and obvious Severe: ballooning of the Severe: extremely swollen lower lid dilated blood vessels conjunctiva 4.0 Incapacitating ocular itching Extremely severe: large, numerous, Not applicable Not applicable dilated blood vessels 616 SECTION D The Eye anatomic location, and treatments will be discussed with each entity. These disease states, symptoms and signs, and treatment are summarized in Table 38.5. Ocular Cicatricial Pemphigoid Introduction. Blistering diseases of the mucocutaneous system are divided as pemphigus, with intraepithelial separation of tissues, and pemphigoid, with separation of tissues at the subepithelial layer.147 An international classification scheme determined that pemphigoid more appropriately be termed immune mediated subepithelial blistering disease (IMSEBD).148 Systemic pemphigoid may have some of its most devas- tating consequences in the eye. The conjunctival component of ocular cicatricial pemphigoid (OCP) is characterized by chronic inflammation, scar formation with fornix shortening and eventual eyelid and eyelash in-turning. The changes seen in OCP are sight threatening (Table 38.5). Patients affected by OCP are usually in the sixth and seventh decade of life. Pemphigoid may begin as early as the third decade of life. There is a moderate to strong female predominance but no racial or geographic predilection.149 Presentation is usually as a chronic conjunctivitis with remitting and relapsing symptoms. The patient generally complains of irritation, burning, tearing, and increased mucus production found as strings in the fornix. The initial ocular sign of OCP may be moderate to severe conjunctival redness. The conjunctiva may then become thick- ened secondary to cellular infiltration and edema fluid, and the epi- thelium will show areas of patchy mucin or cell loss. Subepithelial fibrosis Fig. 38.6 Contact dermatitis of the periocular skin. The distribution is may progress to cause shrinkage and shortening of the depth of the common for the area involved by the use of topically applied eye drops normal fornix. When this occurs in the superior fornix, the small duct- and ointment. ules from the main lacrimal gland may be scarred shut. Eventually, these changes lead to a malposition of the eyelid margin and eyelashes become in-turned and directed toward the conjunctival and corneal surfaces. This contact, along with the contact of the keratinized eyelid Patient Evaluation, Diagnosis, and margin, leads to a mechanical breakdown of the epithelial surface of Differential Diagnosis these structures. Decreased aqueous tear production and a loss of goblet As with allergic ocular processes, the diagnosis of contact dermato- cells in the epithelium leads to further epithelial changes, and the risk conjunctivitis is predicated upon physical examination and a thor- of infection in the cornea is increased. Finally, the conjunctival epithe- ough history including specific questions concerning daily activities, lium may grow beyond the limbus onto the cornea and form a vascu- medications, contact lens products, eye drops, cosmetics, occupa- larized pannus. This likely represents a loss of cornea epithelial stem tion, and hobbies using the previous list of culprit irritants and cell reserve at the limbus. antigens as a guide. The differential diagnosis may include ulcer- The diagnosis of OCP requires a conjunctival biopsy. Light micro- ative blepharoconjunctivitis from staphylococcal infection or AKC. scopic and immunohistochemical staining of biopsy specimens not only Several tests are used for identification of specific antigens or irri- forms the basis for diagnosis but also gives insight into the immuno- tants. Patch testing is the most useful diagnostic tool for evidence of pathophysiology of OCP. The inflammatory cell infiltrate in the sub- contact sensitivity of the eye.146 Patch testing is discussed in detail in stantia propria varies. Mast cell and fibroblast numbers are increased. Chapter 34. Along with this cellular infiltration, deposition of collagen is prominent, and complement and antibodies are found at the basement membrane Treatment zone. Further delineation of the immunopathology comes from elec- The best treatment is avoidance of the offending agent(s). Substitution tron microscopy studies which demonstrated basement membrane zone of nonirritating medications (e.g., contact lens solutions and cosmetics) fragmentation in 60% and duplication in 32% of tissue specimens.150 should be attempted when possible. Comfort measures that can be The sensitivity and specificity for use in the diagnosis of the disease taken include cool compresses four to six times per day, avoidance of is unclear.151 hot water and soaps, and application of a low-potency steroid cream The treatment of OCP is systemic and should be a collaboration (rather than ointment, which can be irritating to the eye) over the between medical and ophthalmology physicians. Determination of other affected area. Topical steroid drops may be indicated. sites of involvement must be performed prior to initiating any treat- ment. Careful attention to symptoms and signs of involvement of skin, nose, oral mucosa, esophagus, trachea, gut, anus, and urethra must be OTHER IMMUNOLOGIC DISEASES OF THE EYE sought. The goal of therapy in the ocular disease should include aboli- It is beyond the scope of this chapter to approach this broad topic by tion of all conjunctival redness in the absence of mechanical aggravating discussing the ophthalmic manifestations of all immune-mediated dis- factors. Mild early disease may respond to oral dapsone. Severe ocular eases. Rather, in this section, diseases localized to the eye with evidence disease likely will require oral steroids and cytotoxic therapy. The use for immune mediation and having importance to the reader will be of intravenous immunoglobulin or biologic agents such as etanercept discussed. Emphasis is placed on the systemic disease presentation that has been reported.152 Rituximab alone or in conjunction with intrave- may accompany these disease entities. The diseases will be classified by nous immunoglobulin (IVIG) is shown to be effective.153 Careful  CHAPTER 38 Allergic and Immunologic Diseases of the Eye 617 TABLE 38.5 Immunologic Diseases of the Eye Disease Clinical Parameters Signs/Symptoms Treatment Ocular cicatricial Systemic pemphigoid Severe conjunctival redness Mild: pemphigoid Females predominate Chronic conjunctivitis Dapsone Peak incidence 60-70 years of age Mucous discharge Severe: Conjunctival scarring Systemic steroids In-turning eyelids and eyelashes Immunosuppressive drugs Breakdown of corneal and conjunctival epithelium Sight threatening Peripheral ulcerative Mild: Mild: Mild: keratitis Both females and males Pain Topical steroids and Any age Photophobia antibiotics Example: associated with Staphylococcal Tearing Necrotizing: blepharitis Redness Topical steroids Necrotizing: Peripheral infiltrate on ocular exam Systemic steroids and other Mooren ulcer Not sight threatening immunosuppressive drugs Both females and males Necrotizing: Surgical intervention Adults Pain Unilateral involvement (worldwide) Photophobia Bilateral involvement (African males) Tearing History of infectious ocular disease Redness History of rheumatic disease Perilimbal ulceration Sight threatening Episcleritis Females predominate Conjunctival redness Cool compress Peak incidence 40 years of age Diffuse or nodular Treat associated blepharitis Minimal pain Artificial tears Not sight threatening Topical NSAIDS Topical steroids Scleritis Females predominate Anterior scleritis: Topical steroids ineffective Peak incidence 40 years of age, rare in Deep, boring pain Periocular steroid injection children Diffuse ocular redness acceptable Anterior scleritis: diffuse, nodular, necrotizing Raised nodules Oral NSAIDs, systemic steroids, Posterior scleritis: scleritis associated with Scleral ulceration immunosuppressive drugs systemic disease, rarely with ocular Necrotizing scleritis: infection (40%) Sight threatening Posterior scleritis: Pain with eye movement Sight threatening Uveitis Associated with systemic and infectious Anterior: Anterior: disease (40%) Redness Topical steroids All ages Pain Intermediate: Occurrence: