Vernal Keratoconjunctivitis

Etiology

Vernal keratoconjunctivitis is a recurrent, bilateral disorder. VKC is more commonly present in males and is most commonly seen after five years. Most cases show remission over the years and are usually resolved by puberty. Few may develop atopic keratoconjunctivitis over the years. VKC is more commonly seen in warm and dry climates. There is also a seasonal variation in these patients, with peak incidence occurring in the spring and summer. These symptoms might become perennial over the years. Thus more chronic the disease, the higher are the chances of symptoms becoming persistent.[5]

There is often a history of atopy present in these patients. Family history of atopy might be positive in close to 49% of these cases. Thus, a genetic link has also been suggested. Apart from personal allergy history, other predisposing factors include male gender, close contact with animals, and increased exposure to dust and sunlight.[6] 

Both IgE-mediated and cell-mediated immune mechanisms are thought to be responsible for these exacerbations. Activated eosinophils have also been implicated in the pathophysiology of VKC. Gabrielides also showed the consistent presence of eosinophils in the conjunctival scrapings of VKC patients. Additionally, the role of type 4 hypersensitivity mediated by CD4 T helper cells has also been highlighted through a few studies. Immunomodulators like interleukins 4, 5, 13, and fibroblast growth factors have also been implicated. There is also reported over-expression of cytokines and chemokines in the conjunctiva of these patients.[7]

Epidemiology

The prevalence of vernal keratoconjunctivitis varies from region to region. It is more commonly seen in tropical and sub-tropical countries and is more prevalent in warm and dry areas. The prevalence reported from cooler countries like the United States as 0.29/10000 population. A prevalence varying from 1.2 to 12.6 cases per 10000 have been reported from Europe. The disease is much more common in countries like Africa, with a reported prevalence varying from 2 to 37%.[6]

The prevalence of corneal complications, thus predisposing to blindness-related sequalae, also varies from region to region. The prevalence rates reported from Europe range from 0.30-2.26. While those reported from Italy vary from 0.4 to 4.8, and from Norway to as low as 0.1 to 1.0.[8] 

VKC is more common in males. A study done in Ethiopia showed that males were 4.23 times more likely to get affected by VKC than females in their study.[6] Another study from Rwanda found odds of 1.7 for males getting affected compared to females. PMID: 21976577 Similar results with higher prevalence among males have also been reported from Italy.[9]

Pathophysiology

In vernal keratoconjunctivitis, multiple papillae are seen in the upper tarsal conjunctiva. The underlying pathological process involves hyperplasia of the conjunctival epithelium. These hyperplastic tissues send projections downwards into the subepithelial tissue. The adenoid layer shows marked cellular infiltration by eosinophils, plasma cells, lymphocytes, and histiocytes. The fibroblasts show proliferative changes, which later undergo hyaline changes. These factors are responsible for the inflammatory process and are involved in tissue remodeling, resulting in giant papillae seen in VKC.[7]

History and Physical

Vernal keratoconjunctivitis is a severe form of allergic disease characterized by marked itching. This is more commonly seen in young boys. The common symptoms include photophobia, burning, foreign body sensation, mucoid discharge, and tearing. Parents also complain about children rubbing their eyes frequently and increasing blinking. The clinical examination findings vary based on the type of disease, further dependent on the geographical location.[10]

Palpebral disease- In the early stages, there is conjunctival hyperemia and velvety papillary hypertrophy of the superior tarsal plate. In the intense disease, flat polygonal macropapillae, which are <1mm in size, are seen along with the whitish inflammatory disease. With further disease progression, these can form giant papillae that are>1mm in size and result from rupture of the dividing septa. Mucoid deposits can occur between giant papillae. The milder form of the pathology is characterized by minimal conjunctival congestion and decreased mucus production.[11]

The bulbar disease-The bulbar disease is also called limbal disease and is particularly more common and severe in tropical regions. This is characterized by congestion of the bulbar conjunctiva in the interpalpebral area. Gelatinous thickened papillae can form around the limbus and are associated with apically located whitish cellular collections known as Horner Tranta Spots.[12]

Corneal signs – Keratopathy is more commonly associated with palpebral disease and can present as superficial punctate epithelial erosions or epithelial macroerosions. The macroerosions usually result from epithelial toxicity from infiltration of inflammatory cytokines and secondary to direct traumatic mechanical effect from papillae. Severe forms can result in plaques and shield ulcers. These can significantly affect visual acuity. These shield ulcers are difficult to heal and can often result in subepithelial scars or keratinization. The scars can be central or peripheral, oval and grey in color, and affect the vision. Shield ulcers are more common in palpebral or mixed forms of the disease and result when the underlying Bowman's membrane is exposed and becomes coated with mucoid discharge and calcium phosphate, resulting in delayed healing and wetting. Shield ulcers should be aggressively treated to prevent secondary bacterial keratopathy.[13] 

Pseudogerontoxon is characterized by a paralimbal band of superficial scarring adjacent to the inflamed limbus resulting from recurrent limbal disease. It usually mimics arcus senalis. VKC is also associated with corneal ectasias, particularly keratoconus, which results from persistent eye rubbing and occasionally superficial vascularization. Associated bilateral herpes simplex keratitis has also been reported.[14]

Lid signs - Blepharitis is often associated with patients with VKC. Some cases might be seen with eczema or maceration of the lid. Subconjunctival fibrosis and symblepharon can rarely develop due to the inflammatory sequelae.[15]

Evaluation

The diagnosis of vernal keratoconjunctivitis is based on clinical examination. The typical history and clinical signs lead to a straightforward diagnosis in most cases. Different staining techniques and associated scoring systems have been described to grade the severity of VKC. The fluorescein stain, lissamine green stain, and confocal microscopy are a few evaluation techniques that help score the severity and grade of involvement. Studies have proven that Oxford scores and Van Bijsterveld scores for evaluating epithelial damage are useful in patients with VKC. Further, the VKC-Collaborative Longitudinal Evaluation of Keratoconus Study (VKC-CLEK) was found to be useful in assessing both limbal and tarsal epithelial damage in VKC patients.[16] 

Corneal topography is an additional investigation that should be considered in VKC patients. The use of videokeratography based on the Placido disc-based system has been proven useful in the early detection and prevention of severe forms of keratoconus. These investigations not only help detect subclinical keratoconus but also provide an opportunity for timely management of these cases and prevent further progression.[17] Occasionally additional lab tests in the form of conjunctival scrapings might be advised in patients with diagnostic dilemmas or not responding to the routine treatment. The conjunctival scraping will show the presence of eosinophils infiltrating the conjunctival epithelium. Additionally, determination of IgE levels, as well as skin tests to look for specific antigens, can be considered, but the usefulness of these tests is limited.

Treatment / Management

The treatment of vernal keratoconjunctivitis depends on the extent and severity of the disease at the time of presentation. The management may vary from conservative treatment to surgical interventions.

Conservative treatment – The foremost step in managing these patients shall be an attempt to remove any possible allergens in the patient’s surroundings. Cold compresses have a soothing effect.[10] Lid scrubs also form the first line of treatment. Dark goggles are helpful to prevent excess glare and photophobia and help prevent exposure to allergens in the surrounding environment. If the disease is recalcitrant, the patient might need to change from hot, windy areas to cold areas.

Medical treatment – In cases with moderate severity, topical mast cell stabilizers like sodium cromoglycate (2%), sodium nedocromil (2%), lodoxamide are helpful.[18] These can be used with topical antihistaminic eye drops, which act on H1 receptors like olopatadine and alcaftadinie.[19](A1)

Dual-action drops with H-1 blockers and mast cell stabilizers are preferred for moderate to severe diseases. These give the advantage of the immediate onset of action and have a long-term disease-modifying action. Topical nonsteroidal anti-inflammatory agents have also shown a beneficial effect in patients with VKC.[20]

Topical corticosteroids, especially low absorptions steroids like fluorometholone, loteprednol, remexolone, are safe alternatives. Severe cases might need more robust alternatives like dexamethasone or betamethasone. Topical steroids need a quick taper and close monitoring for intraocular pressure.

For patients with recurrent episodes, steroid-sparing agents are a better alternative. Topical immunomodulators like cyclosporin (0.05 to 2%) and tacrolimus (0.1%) are the most commonly used in this class.[2][4] These act by decreasing the inflammatory cytokines. Cyclosporine acts by blocking the T helper two cells, thus blocking lymphocyte proliferation.[21][22] It also works by inhibiting histamine release from mast cells and basophils and reducing the conjunctival fibroblast proliferation and interleukin 1b production.[23](A1)

Systemic treatment may be necessary for a few patients with VKC. These may be particularly useful in patients with a history of an associated atopic disease like atopic dermatitis or asthma. Drugs like montelukast, a leukotriene receptor inhibitor, which acts by inhibiting interleukin-10 helpful in treating asthma, have demonstrated benefits by reducing signs and symptoms among VKC patients.[24] Another monoclonal antibody, dupilumab, which acts by inhibiting interleukin-4 receptors, a drug used to treat atopic dermatitis, has also proven beneficial. Omalizumab, another anti-IgE monoclonal antibody, has been used off-label among recalcitrant cases of VKC.[25][26](B2)

Differential Diagnosis

The close differentials of vernal keratoconjunctivitis include all types of allergic conjunctivitis, including seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis, giant papillary conjunctivitis. Most of these are IgE mediated responses except giant papillary conjunctivitis. None have gender predilection, except AKC and VKC, which are more prevalent among males. History and physical examination often help in distinguishing between these clinical entities.

The closest differential of VKC is AKC. The differentiating features include early age of onset in VKC in early teens compared to 20-50 years in AKC. AKC is more commonly associated with asthma, rhinitis, dermatitis. AKC is more chronic and often results in conjunctival cicatrization, whereas VKC episodes are usually self-limiting and do not result in severe vision-threatening sequelae.[19] VKC is associated with increased goblet cells compared to decrease goblet cells in AKC.

Toxicity and Adverse Effect Management

Close monitoring of intraocular pressures is essential in treating patients with topical corticosteroids. Steroid-induced glaucoma is common among patients on long-term treatment, so intraocular pressures should be assessed on regular follow-up visits.[27] Cataract, though rare, has also been reported as a side effect of steroids among VKC patients.

Prognosis

Vernal keratoconjunctivitis is generally a self-limiting disease. There occurs a spontaneous resolution of symptoms around puberty.[28][29] Usually, the course is benign with no vision-threatening sequelae. Rarely, complications in the form of keratoconus, shield ulcers, corneal scarring, and vascularisation may significantly affect visual acuity. Corneal ulcers are reported in close to 9.7% of patients.[30][31] Complications from unmonitored corticosteroids can result in cataracts, or glaucoma can lead to permanent visual impairment. Some cases may persist into adult age in as many as 12% of cases.

Complications

The ocular complications reported among vernal keratoconjunctivitis patients include steroid-induced cataract, steroid-induced glaucoma, irregular astigmatism, keratoconus, acute hydrops, shield ulcer, central corneal scars, and limbal tissue hyperplasia.