E. LEE STOCK and DAVID M. MEISLER
Table Of Contents
|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, Duke-Elder2 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|
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
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.
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.
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.
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 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
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
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
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.34 Thick strands of ropy mucus can be removed, stained, and examined under the microscope. These strands are completely filled with eosinophils and eosinophilic granules.
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.
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
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 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.
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 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.45–47
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 -60°C and -80°C, 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.
Surgical removal of a plaque in the base of a vernal ulcer preventing re-epithelialization 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.
Several authors have reported success with ß-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)
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
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
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 1442–1460. New York, Pergamon Press, 1990