Allergic Conjunctivitis

Definition
Conjunctivitis is inflammation of the conjunctiva, the mucous membrane lining the anterior sclera and inner eyelid surfaces, seen in the broad spectrum of conditions, including allergy. Allergic inflammation of the ocular surface (the lid margins, conjunctiva and cornea is one of the commonest eye disorders. In its mildest form, the conjunctiva becomes inflamed in response to a transient allergen (e.g. pollen in seasonal allergic conjunctivitis), or A persistent allergen (e.g. house dust mite in perennial allergic conjunctivitis) producing unpleasant symptoms but not threatening sight. At the other end of the spectrum are disorders with blinding complications such as vernal keratoconjunctivitis and Atopic keratoconjunctivitis.

Classification of Allergic Conjunctivitis

Clinical Features of Allergic conjunctivitis

History is important Other allergic diseases like asthma or eczema suggest allergic conjunctivitis Use of any topical face/eye preparations allergic dermatoconjunctivitis Seasonal history suggest hay fever caused by grass, tree or weed pollen, perennial (all year round) symptoms suggest house dust mites, pets especially cats or moulds Use of Antihistamines may alter clinical picture Contact lens use irritant or allergic reaction to lens solutions Hallmark symptom of all types of allergic conjunctivitis is itching (pruritus) more prominent in acute cases Photophobia with or without decreased visual acuity, usually means keratitis is present It is important to remember that the eyes can be predominantly affected in hay fever, with less rhinitis symptoms, also when patient have been on nasal steroids they will present with conjunctivitis only. Examination Usually bilateral redness of conjunctiva with swelling (chemosis), periorbital swelling, mucoid discharge There is often eyelid eczema Three types of conjunctival reaction: Follicles - these appear as small, pale, elevated nodules, most marked in lower tarsal conjunctiva Papillae - are less specific red spots. Each papilla has a central vessel running to the surface Giant Papillae - are less common and much more specific. By definition, they are greater than 1mm in diameter, with domed or flat tops. Large polygonal giant papillae with flat tops form the Cobblestone appearance characteristic of vernal conjunctivitis. Key Features of the Diagnosis of IgE-Mediated Allergic Eye Disease Pruritus (itching), which is usually intense Bilateral involvement, and Associated with atopic respiratory tract disease The absence of any of these is strong evidence against allergy. Acute Allergic Conjunctivitis (Seasonal & perennial allergic conjunctivitis) The pruritus usually distinguishes allergic from other causes of conjunctivitis. Can de diagnosed by doing a conjunctival scrape looking for eosinophils. Treatment Options In perennial conjunctivitis, due to house dust mites or cats, avoidance or allergen reduction measures should be first tried along with antihistamines and if this fails immunotherapy should be considered

Seasonal allergic conjunctivitis or Hay Fever Perennial allergic conjunctivitis Atopic keratoconjunctivitis Vernal keratoconjunctivitis Giant papillary conjunctivitis

Vernal Keratoconjunctivitis
This is a chronic, bilateral inflammation of the conjunctiva that is most commonly found in children and adolescents. Males tend to be affected more often than females, and it usually resolves by early adulthood. The effects of vernal conjunctivitis can be so severe that blindness may result. Like allergic conjunctivitis it is immune mediated. It usually occurs in spring and summer months, but in severe cases can be perennial. The most remarkable finding is the intense itching and giant papillae on the tarsal conjunctiva. Ropy mucoid discharge is also a distinguishing sign. Vernal conjunctivitis probably represents a severe and chronic form of allergic conjunctivitis with more intense symptoms and sequelae.
Upper tarsal surface in vernal keratoconjunctivitis showing cobblestone appearance.

Treatment of Vernal conjunctivitis includes: Aggressive use of mast cell stabilisers e.g. sodium cromoglycate Topical antihistamines Topical non steroidal anti-inflammatory agents Topical steroids may be necessary in severe cases

Atopic Keratoconjunctivitis (AKC)

Atopic dermatitis, although usually manifested peripherally, can have significant eye findings. It has been estimated that up to 25% of patients with atopic dermatitis will often have ocular (eye) involvement. Eye involvement in AKC include: Conjunctivitis Keratoconjunctivitis (combine inflammation of the cornea and conjunctiva) causing painful, watering, red eye with blurring of vision Cataracts Increased risk of eye infections
The eyelids in atopic keratoconjunctivitis.

The pathophysiology of AKC is not known, but thought to be combination of Type 1 and Type 4 Hypersensitivity reactions Treatment of AKC Topical steroids for short periods Antihistamines Mast cell stabilizers Cold compresses Careful follow-up to prevent damage to vision

Contact Dermatoconjunctivitis

Contact allergy of the eye and periocular area occurs with a variety of cosmetics, soaps, contact lens solution, and medications. Symptoms include redness of the conjunctiva and periorbital swelling.

Compounds commonly causing allergic contact dermatoconjunctivitis: Neomycin Thiomersal in contact lens solution Atropine Papain Bacitracin Idoxyuridine Ppolymxin B Benzalkonium chloride Investigation: Patch Test Treatment: removal and avoidance of the offending agent, cool compresses, antihistamines, and topical steroids. Secondary infections should be adequately treated.

Giant Papillary Conjunctivitis (GPC)

GPC is increasingly more common with the advent of extended wear lenses. GPC is also associated with sutures in the eye and the presence of foreign body It is thought that the antigen responsible for the inflammatory response is located on the surface of the foreign body. Contact lens wearers secrete a protein that coats the lenses, and it is believed that this protein coating is responsible for the allergic reaction Clinically, GPC is characterized by the presence of large papillae in the tarsal conjunctiva of the upper lid. GPC resembles vernal conjunctivitis, but almost exclusively associated with contact lens wearers. Treatment involves steroid, antihistamines, mast cell stabilizers, frequent enzymatic cleaning of the lens. It will usually stop when the patient stops wearing contact lens or the foreign body is removed.

Management of Allergic Conjunctivitis

The skin prick test should always be done to confirm the culprit allergen, especially if the patient works with animals A Patch Test is indicated in contact dermatoconjunctivitis Immunotherapy for house dust mite, cat, dog, all pollens Non-specific medical therapy: Cold compresses may be all that is necessary in mild seasonal and perennial conjunctivitis Mucolytic drops dissolves the abnormal mucus Treatment of facial eczema in AKC lid margin hygiene Antihistamines conventional topical antihistamine Oral antihistamine preferably non sedating Mast cell stabilizers These compounds are used topically to reduce mast cell degranulation, but also have a wide range of other anti-inflammatory effects that may be relevant. They are usually well tolerated with very few side effects. They offer a preventative action and work most effective if taken before the onset of symptoms, where possible (e.g. at the beginning of the pollen season) or early in the disease process. AS the onset of action is slow (5-7 days) and stinging can occur, patient must be warned that their eyes might feel worse to start with. IN VKC and AKC, mast cell inhibitors act as steroid sparing agents Cromolyn sodium is the longest established of these drugs. And both 2% and 4% drops are available for use up to 4 times per day. Nedocromil sodium is a newer, higher potency mast cell stabilizer that compares favourably to cromolyn and can be used twice daily in SAC and PAC. Lodoxamide is another recently introduced mast cell stabilizer, which may evoke fewer stings than the other. Both nedocromil and lodoxamide have a more rapid onset of action. Steriods Topical steroids are very powerful in controlling allergic conjunctivitis, but have potentially sightthreatening side effects. Steroids are generally contraindicated in SAR & PAR; occasionally they are used in AKC and VKC. Cyclosporine Topical preparation of 2% cyclosporine has been shown to provide a marked reduction in the symptoms and signs of VKC, and cyclosporine is particularly helpful as a steroid-sparing agent. Nonsteroidal anti-inflammatory agents Topical NSAIDs appear to have some beneficial effects in allergic conjunctivitis. Topical NSAID are not as potent as steroids but have the advantage of good ocular safety profile and useful in

treating non sight threatening conditions like SAR and PAR when mast cell stabilizers and antihistamines fail. Surgery Usually limited to the treatment of the sight-reducing corneal disease in AKC & VKC. Laser Surgery This can be useful in corneal plaques.

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Vernal keratoconjunctivitis (VKC) is a chronic and debilitating external ocular disease. The name itself reflects two aspects of the disease. Vernal means youth and spring. In general, children are involved in a large percentage of the cases. The peak age of onset is 8 to 12 years, although 10% of VKC patients are older than 20 at age of onset. 1 A large number of patients with VKC have symptoms that are exacerbated in the spring, possibly due to the increase in the pollen count. However, DukeElder2 suggests that most symptoms appear in the summer rather than in the spring. Most series describe a male preponderance,1 although one series points out a female preponderance of patients with limbal vernal when cases are stratified by sex.3 Back to Top

CLINICAL FINDINGS
CONJUNCTIVA Patients with VKC may be divided into two groups based on clinical presentation: palpebral vernal and limbal vernal. Palpebral vernal involves the upper tarsal conjunctiva and is characterized by cobblestone papillae (i.e., papillae that have enlarged, often having flattened tops (Fig. 1). Papillae can be distinguished from follicles by their red centers; these centers consist of the dilated blood vessel at the core of the papilla surrounded by inflammatory cells. A sequela that may occur in VKC is conjunctival scarring that has a lacy appearance at the base of the old papillae. Although rare, there may be lacy scarring that extends superiorly into the fornix (Fig. 2). On rare occasions there may be conjunctival cysts (Fig. 3) and enough scarring to cause symblepharon formation. Fibrin that is enhanced by heat may accumulate on the giant papillae and is known as the Maxwell-Lyons sign.4

Fig. 1. Clinical photograph of the upper palpebral conjunctiva showing cobblestone papillae with their flat-top appearance.

Fig. 2. Upper lid retracted with a Desmarres retractor showing the cobblestone papillae of the upper tarsal conjunctiva and lacy scarring of the upper fornix.

Fig. 3. Conjunctival cyst at the limbus.

Limbal vernal begins as a thickening and opacification of the limbus. Limbal nodules appear as gelatinous, elevated lesions that may seem to coalesce and become confluent. Horner-Trantas' dots are small white elevated lesions that appear at the apices of limbal excresences that consist of desquamated epithelial cells and eosinophils (Fig. 4). Mixed vernal is a combination of limbal and palpebral lesions. Fig. 4. Limbal vernal: HornerTrantas' dots and elevated gelatinous lesions.

CORNEA Corneal involvement may be severe enough to interrupt a child's education, or if uncontrolled it may cause permanent corneal scarring and loss of vision. Vernal keratitis is characterized by a combination of punctate epithelial erosions and keratitis.5 Punctate epithelial erosions are areas of absent epithelium that stain with fluorescein. Punctate epithelial keratitis is an influx of white cells into the corneal epithelium. The epithelium in this area stains with rose bengal, which stains devitalized cells.6 Keratitis epithelialis of Tobgy7 is the early phase of vernal keratitis, consisting of minute white dots in the epithelium. When the keratitis coalesces, a vernal ulcer is formed. Vernal corneal ulcers, also known as shield ulcers, are usually horizontally oval in orientation and involve the upper third of the cornea (Fig. 5). There is often white material at the base of the ulcer, which has been reported to be mucopolysaccharides. In general, these ulcers are sterile, but there have been rare reports of superimposed infectious corneal ulcers occurring in VKC. Kerr and Stern8 described four patients with VKC who developed bacterial corneal ulcers. These patients showed infiltrates in the cornea, corneal edema, iritis, and hypopyon. Staphylococcus aureus grew out of the ulcer from all four, and three of the four ulcers were polymicrobial. These ulcers were differentiated from vernal shield ulcers, which are indolent and often have a plaque at the base. Fig. 5. Vernal ulcer that is horizontal in upper one third of cornea.END

MUCUS VKC is often accompanied by a thick, tenacious mucous discharge that may be so thick that it adheres to the giant cobblestones of the upper tarsus. When removed, it may form a cast of the cobblestones. Patients report symptomatic relief when the stringy, ropy secretions are removed from the cul-de-sac. In addition, the combination of punctate epithelial keratitis and increased mucus are the necessary ingredients for filamentary keratitis. Back to Top

PATHOPHYSIOLOGY

TYPE I HYPERSENSITIVITY There is evidence that VKC is an allergic disease, appearing in patients who are atopic (i.e., having signs of asthma, eczema, or hay fever). The mechanism of disease involves fixation of IgE molecules on the surface of mast cells and release of mediators, including histamine and prostaglandins.9 Frankland and Easty10 noted that 93% of their 35 patients from the United Kingdom had manifestations of atopic disease, including asthma, eczema, or hay fever, but 7% did not. In another study, serum IgE levels were elevated in 75% of patients with VKC.11 These authors suggested two subgroups based on the presence or absence of IgE in the serum. In support of this concept, Zavaro and colleagues12 studied two patients in depth, one of whom had evidence of atopic disease, including elevated serum and tear IgE; the other had no evidence of atopic disease. Further support of the concept of two subclasses of VKC was given by Neumann and associates,1 who suggested that the prevalence of atopy in their VKC population in Israel was the same as in the general population (10%). However, Zavaro and colleagues12 stated that 80% of their Israeli patients had elevated IgE in the tears and marked eosinophilic infiltration of the conjunctiva. Abu El-Asrar and co-workers13 investigated the immunopathology of VKC patients. They found numerous plasma cells that were producing IgA and IgG, but rarely IgE. However, they also found numerous mast cells with IgE on the surface. Allansmith14 reported IgE as well as IgA and IgD plasma cells in the tarsal conjunctiva of patients with VKC. Allansmith and Frick15 were among the first to provide laboratory evidence of VKC as an allergic disease when they noted antibodies to grass in the tears of patients with VKC. Increased IgE levels in the tears of patients with VKC have been reported,14 although these authors believed that the increased tear levels were a function of increased serum IgE levels. Subsequently, specific IgE antibodies to pollen allergens were identified in the tears,16 and there have been other reports of specific IgE antibodies in the tears.17 In addition, these investigators found higher levels of antibody in the tears than in the serum, suggesting local production of antibody in the conjunctiva. MEDIATORS Mediators of immediate hypersensitivity reactions have been found in the tears of patients with VKC. Histamine levels in the tears have been found to be elevated.18 The role of eosinophil granule major basic protein as a mediator of the immunopathology of VKC has been investigated. Eosinophil granule major basic protein is the main protein found in the eosinophil granule. It causes desquamation of respiratory epithelium in vitro and mast cell degranulation, and is deposited at sites of damage in vivo. It has been found in the tears of patients with VKC,19 in the tissue,20 and in corneal ulcers of these patients.21

DELAYED HYPERSENSITIVITY It has been suggested that there is a cell-mediated component in vernal conjunctivitis as well, and this has been substantiated by studies of the conjunctiva of patients with vernal conjunctivitis.22 The increased number of T4 helper/inducer cells has been confirmed, and further study has showed these cells to be the type that can induce the production of IgE antibody.23 Abu El-Asrar found numerous stromal lymphocytes.13 A specific type of delayed hypersensitivity known as cutaneous basophil hypersensitivity has also been implicated,24 and in an animal model the influx of eosinophils as well as basophils has added evidence that this type of hypersensitivity may be operant.25 ASSOCIATED DISEASES Butrus and colleagues26 described ten patients with the hyperimmunoglobulin E syndrome, which comprises chronic pruritic dermatitis, marked elevation in systemic IgE levels, severe recurrent systemic infections, and coarse facial features. Four of these patients had systemic atopic symptoms consistent with asthma or allergic rhinoconjunctivitis. Three of these four had ocular findings similar to those of vernal conjunctivitis, including papillary hypertrophy of the upper tarsal conjunctiva, corneal shield ulcer, and Trantas' dots. There is also a strong association between ectatic corneal disease, such as keratoconus and pellucid marginal degeneration, and VKC.27 Back to Top

PATHOLOGY
HISTORY In the nineteenth century, it was generally thought that VKC was a lymphoid disease, possibly a neoplasm.28 In the early twentieth century, Herbert29 pointed out the presence of eosinophils in tissue obtained from patients with vernal conjunctivitis. Axenfeld's 1907 study demonstrated the cellular infiltration that included lymphoid cells and plasma cells. He emphasized the increased visibility of the mast cells and the decreased number of plasma cells in the winter when the disease was inactive.30 PATHOLOGY OF PALPEBRAL VERNAL The histopathology of 100 cases of VKC from the Institute of Ophthalmology in London was reviewed by Morgan.31 He noted that the main feature was the infiltration of inflammatory cells, especially lymphocytes, eosinophils, and plasma cells. Later on in the disease, collagen fibers are deposited. When the patient is in remission, the plasma cells disintegrate and the mast cells become more numerous. Allansmith32 noted that many mast cells are actively degranulating in VKC and for that reason cannot be visualized by light microscopy, but the mast cell membranes can be seen on electron microscopy. This was

confirmed by Abu El-Asrar,13 who noted that the number of cells that had surface staining with IgE was larger than the number of cells identified by light microscopy. After treatment with corticosteroids, there was less infiltration of inflammatory cells and an absence of eosinophils, and there was a lesser degree of degranulation of mast cells.33 Recent evidence has suggested that mast cells are not homogeneous.34Thick strands of ropy mucus can be removed, stained, and examined under the microscope. These strands are completely filled with eosinophils and eosinophilic granules. Back to Top

TREATMENT
NONSPECIFIC Cold compresses may alleviate the itching in vernal conjunctivitis when it is mild. However, when the disease is more severe, this treatment is usually not effective by itself. ANTIHISTAMINE-VASOCONSTRICTORS These preparations may have some role in the treatment of mild vernal conjunctivitis; however, in the face of onset of any keratitis, they do not have the potency necessary to control the inflammation. MAST CELL STABILIZERS In recent years, mast cell stabilizers have been introduced for the treatment of VKC. Examination of the first report of cromolyn in VKC is important to understand possible differences between various studies.35 In this pioneering study, most patients with VKC could be controlled with cromolyn alone. However, some required short-term corticosteroids in addition to cromolyn, and others required long-term corticosteroids in addition to cromolyn. This emphasizes the prophylactic nature of the drug and its steroid-sparing qualities. However, cromolyn is usually not adequate when the eye is severely inflamed or when there is a vernal ulcer. In these cases, the inflammation should be controlled with topical corticosteroids, and cromolyn should be added as adjunctive therapy to allow the corticosteroids to be tapered. Other mast cell stabilizers have been evaluated. Nedocromil drops have been shown to be effective when compared with placebo,36 and lodoxamide (Alomide) has been shown to be more effective than cromolyn in the treatment of VKC.37 PROSTAGLANDIN INHIBITORS Coincident with his studies on the effect of prostaglandins on the outer eye, Abelson and his co-workers38 suggested the use of oral aspirin in the treatment of VKC. The efficacy of aspirin was also confirmed in other studies,39,40 and in the latter study it was thought to be more long-lasting

than corticosteroids. Gupta and associates41 treated 25 VKC patients with 1% indomethacin drops, and 21 of their patients were improved on this regimen. Ketorolac (Acular) is a nonsteroidal anti-inflammatory drug that blocks the release of prostaglandins.42 Its role in VKC has yet to be determined. CORTICOSTEROIDS Corticosteroids inhibit mediator biosynthesis and disrupt intercellular communications by preventing the release of lymphokines.43 They are the most effective and the best-proved treatment for VKC, especially when the keratitis is active. Corticosteroids can be administered in drop form, and the treatment regimen is varied, depending on the severity of the disease. In severe conjunctivitis, hourly corticosteroid drop administration may be necessary. In severe cases, systemic corticosteroids may be given to bring the inflammation under control. Patients should be monitored for the complications of corticosteroids, including glaucoma, cataract, and external ocular infections, because there is already an increased incidence of cataract and infections in patients who are atopic. ACETYLCYSTEINE One of the common clinical findings is the tenacious mucus that develops. This may take any of three forms: mucus adhering to the cobblestones, thick, ropy strands of mucus, or filamentary keratitis. Acetylcysteine is known to break the disulfide bonds, thereby dissolving the mucus, and it is effective for all three types of excessive mucus. It is formulated from commercially available Mucomyst, diluted to a 5% or 10% solution with artificial tears, and is applied four times a day. IMMUNOSUPPRESSIVE AGENTS Immunosuppressive medication may be beneficial. Cyclosporin A is a potent immunosuppressive drug used in the prevention of transplant rejections. Cyclosporin A binds to cyclophilin, an intracellular protein, which in turn prevents the formation of interleukin-2 and the subsequent recruitment of activated T cells.44 It has been used successfully in several studies to treat VKC.4547 CRYOTHERAPY Several reports have advocated the use of cryotherapy in the treatment of VKC. Sankarkumar and colleagues48 treated the conjunctiva of 30 eyes in 15 patients with a glaucoma probe at -60C and -80C, repeating the freeze-thaw cycle two to three times. They concluded that cryotherapy was helpful in the management of VKC. However, they also gave the patients 0.5 to 1.5 g of aspirin. Therefore, it is difficult to distinguish the effect of the cryotherapy from that of the aspirin.

SURGERY Surgical removal of a plaque in the base of a vernal ulcer preventing reepithelialization may promote healing. Tarsectomy with or without mucous membrane graft has been suggested to physically remove the cobblestone papillae.49 However, these reports appear to lack long-term follow-up. Mucous membrane grafting has been reported to improve symptoms in vernal conjunctivitis.50 Although there has been controversy in the literature regarding this procedure, Tse and associates51 found this procedure successful and long-lasting with follow-up. Buckley,52 on the other hand, warns that distorting the tarsus can cause adverse changes in eyelid position. -IRRADIATION Several authors have reported success with -irradiation in the treatment of VKC.53 However, one of the authors of this article (ELS) has seen permanent scarring from this treatment, and the lack of publications in the modern literature suggests that this mode of therapy no longer has a place in the treatment of VKC.

Supported in part by a Department of Veterans' Affairs Research Service Merit Review Grant. (ELS) Back to Top

REFERENCES
1. Neumann E, Gutmann MJ, Blumenkrantz N et al: A review of four hundred cases of vernal conjunctivitis. Am J Ophthalmol 147:166, 1959 2. Duke-Elder S: Diseases of the outer eye, Part I. In Duke-Elder S (ed): System of Ophthalmology, p 476. London, Henry Kimpton, 1965 3. Tuft SJ, Dart JK, Kemeny M: Limbal vernal keratoconjunctivitis: Clinical characteristics and immunoglobulin E expression compared with palpebral vernal. Eye 3:420, 1989 4. Donshik PC, Williams HE: Ocular allergy. In Smolin G, Thoft R (eds): The Cornea, p 355. Boston, Little, Brown, 1994 5. Jones B: Vernal keratitis. Trans Ophthalmol Soc UK 81:215, 1961 6. Jones B: The differential diagnosis of punctate keratitis. Trans Ophthalmol Soc UK 80:665, 1960 7. Arffa RC: Immunologic disorders. In Arffa RC (ed): Grayson's Diseases of the Cornea. St. Louis, CV Mosby, 1991

8. Kerr N, Stern GA: Bacterial keratitis associated with vernal keratoconjunctivitis. Cornea 11:355, 1992 9. Stock EL: Immunological mechanisms of allergic disease. Int Ophthalmol Clin 29:262, 1988 10. Frankland AW, Easty D: Vernal keratoconjunctivitis: An atopic disease. Trans Ophthalmol Soc UK 91:479, 1971 11. Easty D, Birkenshaw M, Merrett T et al: Immunological investigations in vernal eye disease. Trans Ophthalmol Soc UK 190:98, 1980 12. Zavaro A, Baryishak YR, Samra Z et al: Extrinsic and idiopathic vernal keratoconjunctivitis? Two cases with dissimilar immunopathology. Br J Ophthalmol 67:742, 1983 13. Abu El-Asrar AM, Van den Oord JJ, Geboes K et al: Immunopathological study of vernal keratoconjunctivitis. Graefes Arch Clin Exp Ophthalmol 227:374, 1989 14. Allansmith MR, Hahn GS, Simon MA: Tissue, tear, and serum IgE concentrations in vernal conjunctivitis. Am J Ophthalmol 81:506, 1976 15. Allansmith MR, Frick OL: Antibodies to grass in vernal conjunctivitis. J Allergy 34:535, 1963 16. Ballow M, Mendelson L: Specific immunoglobulin E antibodies in tear secretions of patients with vernal conjunctivitis. J Allergy Clin Immunol 66:112, 1980 17. Ballow M, Donshik PC, Mendelson L et al: IgG specific antibodies to rye grass and ragweed pollen antigens in the tear secretions of patients with vernal conjunctivitis. Am J Ophthalmol 95:161, 1983 18. Abelson MB, Soter NA, Simon MA: Histamine in human tears. Am J Ophthalmol 83:417, 1977 19. Udell IR, Gleich GJ, Allansmith MR et al: Eosinophil granule major basic protein and Charcot-Leyden crystal protein in human tears. Am J Ophthalmol 92:824, 1981 20. Trocme SD, Kephart GM, Allansmith MA et al: Conjunctival deposition of eosinophil granule major basic protein in vernal keratoconjunctivitis and contact lens-associated giant papillary conjunctivitis. Am J Ophthalmol 108:57, 1989 21. Trocm SD, Kephart GM, Bourne WM et al: Eosinophil granule major basic protein deposition in corneal ulcers associated with vernal keratoconjunctivitis. Am J Ophthalmol 115:640, 1993

22. Bhan AK, Fujikawa LS, Foster CS: T-cell subsets and Langerhans cells in normal and diseased conjunctiva. Am J Ophthalmol 94:205, 1982 23. Maggi E, Biswas P, Del Prete G et al: Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J Immunol 146:1169, 1991 24. Collin HB, Allansmith MR: Basophils in vernal conjunctivitis in humans: An electron microscope study. Invest Ophthalmol Vis Sci 16:858, 1977 25. Stock EL, Meisler DM: Cutaneous basophil hypersensitivity in the guinea pig conjunctiva. Curr Eye Res 2:887, 1982/1983 26. Butrus SI, Leung DYM, Gellis S et al: Vernal conjunctivitis in the hyperimmunoglobulin E syndrome. Ophthalmology 91:1213, 1984 27. Cameron JA, Al-Rajhi AA, Badr IA: Corneal ectasia in vernal keratoconjunctivitis. Ophthalmology 96:1615, 1989 28. Beigelman MN: Vernal Conjunctivitis. Los Angeles, University of Southern California Press, 1950 29. Herbert H: Preliminary notes on the pathology and diagnosis of spring catarrh. Br Med J II:735, 1903 30. Axenfeld T: Rapport sur le catarrhe printanier. Bull Mem Soc Fr Ophtalmol 24:1, 1907 31. Morgan G: The pathology of vernal conjunctivitis. Trans Ophthalmol Soc UK 91:467, 1971 32. Allansmith MR, Baird RS: Percentage of degranulated mast cells in vernal conjunctivitis and giant papillary conjunctivitis associated with contact lens wear. Am J Ophthalmol 9:71, 1981 33. Easty DL, Birkenshaw M, Merrett T et al: Immunologic investigations in vernal eye disease. Trans Ophthalmol Soc UK 190:98, 1980 34. Irani AA, Schecter NM, Craig SS et al: Two types of mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA 83:4464, 1986 35. Easty D, Rice NSC, Jones B: Disodium cromoglycate (Intal) in the treatment of vernal keratoconjunctivitis. Trans Ophthalmol Soc UK 91:491, 1971 36. Bonini S, Barney NP, Schiavone M et al: Effectiveness of nedocromil sodium 2% eyedrops on clinical symptoms and tear fluid cytology of

patients with vernal conjunctivitis. Eye 65:648, 1992 37. Caldwell DR, Philippe V, Hartwich-Young R et al: Efficacy and safety of lodoxamide 0.1% vs cromolyn sodium 4% in patients with vernal keratoconjunctivitis. Am J Ophthalmol 113:632, 1992 38. Abelson MB, Butrus S, Weston JH: Aspirin therapy in vernal conjunctivitis. Am J Ophthalmol 95:502, 1983 39. Meyer E, Kraus E, Zonis S: Efficacy of antiprostaglandin therapy in vernal conjunctivitis. Br J Ophthalmol 71:497, 1987 40. Lemrini F, Dafrallah L, Sebbahi et al: Traitement de la conjonctivite printanire par l'aspirine. Rev Int Trach Pathol Ocul Trop Subtrop Sante Publique 66:119, 1989 41. Gupta S, Khurana AK, Ahluwalia BK et al: Topical indomethacin for vernal keratoconjunctivitis. Acta Ophthalmol 69:95, 1991 42. Tinkelman DG, Rupp G, Kaufman H et al: Double masked, paired comparison clinical study of ketorolac tromethamine 0.5% ophthalmic solution compared with placebo eye drops in the treatment of seasonal allergic conjunctivitis. Surv Ophthalmol (suppl) 38:133, 1993 43. Haynes RC Jr: Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormone. In Gilman AG, Rail TW, Nies AS et al (eds): The Pharmacological Basis of Therapeutics, 8th ed, pp 14421460. New York, Pergamon Press, 1990 44. Stock EL, Pendleton RB: Pharmacological treatment of ocular allergic diseases. Int Ophthalmol Clin 33:47, 1993 45. BenEzra D, Pe'er J, Brodsky M et al: Cyclosporin eye drops for the treatment of severe vernal keratoconjunctivitis. Am J Ophthalmol 101:278, 1986 46. Bleik JH, Tabbara KF: Topical cyclosporine in vernal keratoconjunctivitis. Ophthalmology 98:1679, 1991 47. Secchi AG, Tognon MS, Leonardi A: Topical use of cyclosporine in the treatment of vernal keratoconjunctivitis. Am J Ophthalmol 110:641, 1990 48. Sankarkumar T, Panda A, Angra SK: Efficacy of cryotherapy in vernal catarrh. Am J Ophthalmol 124:253, 1992 49. Sugar HS: Tarsectomy for proliferative palpebral vernal conjunctivitis. Am J Ophthalmol 53:429, 1962 50. Cross AG: Surgical treatment of persistent vernal catarrh. Trans

Ophthalmol Soc UK 79:45, 1959 51. Tse DT, Mandelbaum S, Epstein S et al: Mucous membrane grafting for severe palpebral vernal conjunctivitis. Arch Ophthalmol 101:1879, 1983 52. Buckley RJ: Vernal keratoconjunctivitis. Int Ophthalmol Clin 28:303, 1988 53. Hughes WF Jr: Beta radiation therapy in ophthalmology. Trans Am Ophthalmol Soc 50:469, 1952

http://www.oculist.net/downaton502/prof/ebook/duanes/pages/v4/v4c009.html http://medchrome.com/minor/ophthalmology/vernal-keratoconjunctivitis-vkc-or-spring-catarrah/ http://www.mims.com/Singapore/pub/topic/Medical%20Progress/201204/Conjunctivitis%20Dont%20Miss%20the%20Serious%20Causes%20%20 http://openi.nlm.nih.gov/detailedresult.php?img=2629892_kjo-21-251-g001&req=4 http://secure.pharmacytimes.com/lessons/html/conjunct2001.htm

The ocular surface may exhibit a wide variety of immunologic responses resulting in inflammation of the conjunctiva and cornea. In the Gell and Coombs classification system for various immunologic hypersensitivity reactions, 5 types of reactions are recognized. The major type I hypersensitivity reactions involving the conjunctiva are commonly referred to as allergic conjunctivitis. Diagnosis of allergic conjunctivitis is generally made by thorough history and careful clinical observation (see Clinical). The presence of an antigen starts the allergic cascade, and, thus, avoidance of the offending antigen is the primary behavioral modification for all types of allergic conjunctivitis. In other respects, management of allergic conjunctivitis varies somewhat according to the specific subtype. Allergic conjunctivitis can be treated with a variety of drugs, including topical antihistamines, mast cell stabilizers, nonsteroidal anti-inflammatory drugs, and corticosteroids (see Treatment). See the following for more information:

Acute Hemorrhagic Conjunctivitis Atopic Keratoconjunctivitis Bacterial Conjunctivitis Emergent Treatment of Acute Conjunctivitis Epidemic Keratoconjunctivitis Giant Papillary Conjunctivitis Keratoconjunctivitis Sicca Neonatal Conjunctivitis Superior Limbic Keratoconjunctivitis Viral Conjunctivitis

Immunologic reactions of conjunctiva and cornea

Type I (immediate) hypersensitivity reactions occur when a sensitized individual comes in contact with a specific antigen. Immunoglobulin E (IgE) has a strong affinity for mast cells, and the cross-linking of 2 adjacent IgE molecules by the antigen triggers mast cell degranulation. The mast cells degranulation releases various preformed and newly formed mediators of the inflammatory cascade. Most notable of these inflammatory mediators are histamine, tryptase, chymase, heparin, chondroitin sulfate, prostaglandins, thromboxanes, and leukotrienes. These various inflammatory mediators, together with various chemotactic factors, result in an increase in vascular permeability and migration of eosinophils and neutrophils. This type I hypersensitivity reaction is the most common allergic response of the eye. These immune-derived reactions may be the underlying cause of various ocular conditions, such as cicatricial pemphigoid and Mooren ulcer. Type III hypersensitivity reactions result in antigen-antibody immune complexes, which deposit in tissues and cause inflammation. A classic systemic type III reaction is the Arthus reaction, and ocular type III hypersensitivity reactions include Stevens-Johnson syndrome and marginal infiltrates of the cornea. These type III reactions can often induce a corneal immune (Wesley) ring that dissolves when the inflammatory reaction subsides. Type IV hypersensitivity reactions, also known as cell-mediated immunity, are interceded by T lymphocytes. This inflammatory cell-driven reaction is also referred to as delayed-type hypersensitivity, since its onset is generally after 48 hours, in contrast to the type I reaction, which is an immediate hypersensitivity. Type IV hypersensitivity reactions imply immunocompetence on the part of the individual since an intact immune system is required to mount the cell-mediated response. Ocular examples of type IV hypersensitivity include phlyctenular keratoconjunctivitis, corneal allograft rejection, contact dermatitis, and drug allergies.

Allergic conjunctivitis subtypes

Allergic conjunctivitis may be divided into 5 major subcategories. Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) are commonly grouped together. Vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis (GPC) constitute the remaining subtypes of allergic conjunctivitis. Early diagnosis and treatment will help prevent the rare complications that can occur with this disease.

Prognosis
Since allergic conjunctivitis generally clears up readily, the prognosis is favorable. Complications are very rare, with corneal ulcers or keratoconus occurring rarely. Although allergic conjunctivitis may commonly reoccur, it rarely causes any visual loss.

Patient education
Patients should make every attempt to identify the allergen causing the problem and to avoid the offending antigen. For patient education information, see the Eye and Vision Center, as well as Pinkeye, Eye Allergies, and How to Instill Your Eyedrops.

Pathophysiology
Seasonal and perennial allergic conjunctivitis
Since the conjunctiva is a mucosal surface similar to the nasal mucosa, the same allergens that trigger allergic rhinitis may be involved in the pathogenesis of allergic conjunctivitis. Common airborne antigens, including pollen, grass, and weeds, may provoke the symptoms of acute allergic conjunctivitis, such as ocular itching, redness, burning, and tearing. The main distinction between SAC and PAC, as implied by the names, is the timing of symptoms. Individuals with SAC typically have symptoms of acute allergic conjunctivitis for a defined period of time, that is, in spring, when the predominant airborne allergen is tree pollen; in summer, when the predominant allergen is grass pollen; or in fall, when the predominant allergen is weed pollen. Typically, persons with SAC are symptom-free during the winter months in cooler climates because of the decreased airborne transmission of these allergens. Seasonal allergic conjunctivitis can manifest itself through tear film instability and symptoms of eye discomfort during the pollen season. One study found that outside the pollen season, allergic inflammation did not cause permanent tear film instability.[1] In contrast, individuals with PAC may have symptoms that last the year round; thus, PAC may not be caused exclusively by seasonal allergens, although they may play a role. Other common household allergens, such as dust

mite, cockroach dust, cigarette smoke, airborne allergens, and pet dander, may be responsible for the symptoms of PAC.

Vernal keratoconjunctivitis
VKC is a chronic bilateral inflammation of the conjunctiva, commonly associated with a personal and/or family history of atopy. More than 90% of patients with VKC exhibit one or more atopic conditions, such as asthma, eczema, or seasonal allergic rhinitis.

Atopic keratoconjunctivitis
AKC is a bilateral inflammation of conjunctiva and eyelids, which has a strong association with atopic dermatitis. It is also a type I hypersensitivity disorder with many similarities to VKC, yet AKC is distinct in a number of ways. In 1953, Hogan first described the association between atopic dermatitis and conjunctival inflammation. [2] He reported 5 cases of conjunctival inflammation in male patients with atopic dermatitis.[2] Atopic dermatitis is a common hereditary disorder that usually has its onset in childhood; symptoms may regress with advancing age. Approximately 3% of the population is afflicted with atopic dermatitis, and, of these, approximately 25% have ocular involvement.

Giant papillary conjunctivitis

GPC is an immune-mediated inflammatory disorder of the superior tarsal conjunctiva. As the name implies, the primary finding is the presence of "giant" papillae, which are typically greater than 0.3 mm in diameter. A combination of type I and type IV hypersensitivity reactions may be responsible for the pathogenesis of GPC. It is believed that an antigen is present, in predisposed individuals, which stimulates the immunological reaction and the development of GPC. Prolonged mechanical irritation to the superior tarsal conjunctiva, of the upper lid, from any of a variety of foreign bodies may also be a contributing factor in GPC. Although contact lenses (hard and soft) are the most common irritant, ocular prostheses, extruded scleral buckles, and exposed sutures following previous surgical intervention may also precipitate GPC.

Epidemiology
Allergic conjunctivitis occurs very frequently and is seen most commonly in areas with high seasonal allergens. VKC occurs predominantly in areas with tropical and temperate climates, such as the Mediterranean, the Middle East, and Africa. The limbal form of VKC commonly occurs in dark-skinned individuals from Africa and India.

Sexual and age-related differences in incidence

VKC has a significant male preponderance, typically affecting young males. The onset of VKC is generally in the first decade and persists for the first 2 decades. Symptoms usually peak prior to the onset of puberty and then subside.

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