Vernal keratoconjunctivitis (VKC) or spring catarrh is a chronic, recurrent, bilateral, at times asymmetrical, seasonally exacerbated external ocular inflammation affecting children and young adults. VKC usually begins before the age of 10 years. It generally resolves around puberty, usually about 4-10 years after onset and only rarely may persist beyond the age of 25 years.
It is more common in males than in females. The male preponderance is prominent below 20 years of age but thereafter, male and female ratio of involvement becomes almost equal.
The exact aetiology and pathogenesis is still unclear, although allergic nature of this disease is being accepted for long. Role of genetic predisposition and environmental factors in onset, progression and resolution of this self-limiting disease, but incapacitating at times, is not clear. Occurrence of this disease is not limited to spring, with episodes of reactivity being quite common in winter. Initial seasonal feature turn into perennial (occurring throughout the year) disease after few years.
Patients may have associated atopy (genetic tendency to develop allergic disease) or have a close family history of atopy. Atopic patients often develop asthma, eczema and seasonal allergic rhinitis during infancy.
Although this is not usually a blinding disease, visual impairment may occur if there is corneal involvement.
Patients with VKC have an increased incidence of keratoconus.
Three main clinical types are:-
- Palpebral (Eyelid).
- Limbal (junction between conjunctiva and cornea).
Vernal keratoconjunctivitis has a wide geographical distribution and young people in dry and hot climates are primarily affected.
Basak Samar K, Atlas of Clinical Ophthalmology, 2nd ed. Jaypee Brothers Medical Publishers (P) Ltd, 2013, New Delhi, P. 54.
Kanski,Jack J. Clinical Ophthalmology, A Systematic Approach .Third Edition.UK. Butterworth Heinemann, 1994.
Patients with VKC may have several episodes of active inflammation throughout the year, but symptoms are characteristically worse during spring and summer.
Patient may have following symptoms in eyes:
- Itching is the most important and most common symptom. Itching may vary from mild to intense and is exacerbated by exposure to dust, wind, bright light, hot weather or physical exertion associated with sweating.
- Conjunctival redness.
- Thick mucoid discharge with sticky mucous filaments, called ‘ropy discharge’, is characteristic of VKC.
- Pain and discomfort.
- Foreign body sensation.
- Chemosis (swelling of conjunctiva).
- Photophobia (increased sensitivity to light).
- Blepharospasm (involuntary closure of eyelid muscles).
- Blurring of vision.
- Swelling of lids.
In addition to ocular (eye) symptoms, patient may show symptoms of associated systemic allergic or atopic conditions such as eczema, asthma, rhinitis or urticaria.
The exact aetiology and pathogenesis is still not clear, although allergic nature of this disease is being accepted for long. Role of genetic predisposition and environmental factors in onset, its progression and resolution of this self-limiting disease, is not clear.
Genetics of disease:
No genetic predisposing factor has been identified, but the predominance of VKC in Asia and Africa strengthens the possibility of a genetic predisposition.
Type I (immediate) hypersensitivity reaction occur when a sensitised individual comes into contact with a specific antigen. Immunoglobulin E (IgE) has a strong affinity for mast cells, and the cross-linking of IgE with antigen triggers mast cell degranulation. Mast cell degranulation releases various mediators of inflammatory cascade which results in an increase in vascular permeability and migration of eosinophils and neutrophils.
Family history of allergic disorders and multiple atopic diseases may be present in some patients suffering from VKC.
Conditions which may be associated with VKC are:
- Atopy: Atopy, defined as the presence of allergen-specific IgE antibodies, is common among VKC patients. Asthma is the most common atopic disease found among VKC patients. Other associated atopic diseases may be eczema, rhinitis or urticaria.
- Keratoconus (conical cornea) and acute hydrops (stromal oedema due to leakage of aqueous): Keratoconus and acute hydrops may be associated with VKC.
- Sex-hormone related diseases: Sex-hormone related diseases such as gynaecomastia, mammary fibro-adenoma, polycystic ovary syndrome and autoimmune diseases are also being reported with VKC.
Diagnosis of VKC is based upon typical clinical features, thus many mild or atypical cases may escape diagnosis. Lack of standardised diagnostic criteria regarding the severity of VKC renders this disease more difficult to diagnose and manage.
Despite facts suggesting immune responses in the pathogenesis of VKC, no clinical or laboratory test has evolved to support the diagnosis in atypical cases or predict the course of disease.
History of atopy in patient or the family, elevated serum level of total and specific IgE, higher number of eosinophils and mast cells, increased level of mediators and favourable response to anti-allergic therapy is observed in VKC.
Prevalence of IgE sensitisation is found to be significantly lesser in bulbar as compared to palpebral and mixed type of VKC.
Signs of VKC are mostly confined to conjunctiva and cornea.
- Giant papillae: Classic conjunctival sign in palpebral VKC is the presence of giant papillae. The bluish-white papillae are separated by white connective tissue septa. Papillae, most commonly, occur on superior palpebral conjunctiva, and on rupture of connective tissue septa forms giant papillae. Inferior palpebral conjunctiva is unaffected. Giant papillae assume a flat-top appearance, which is described as ‘cobblestone papillae’. Active disease is characterised by redness, swelling and tightly packed papillae. As the inflammation settles, the papillae become more separated.
- Mucous discharge: A ropy mucous discharge may be present, which commonly is associated with palpebral papillae. Large numbers of eosinophils are present in discharge, indicating presence of extended periods of inflammation.
- Vascular abnormalities.
- Sub-conjunctival scarring.
- Conjunctival inclusion cysts.
- Mechanical ptosis (drooping of upper eyelids): Large papillae may cause mechanical ptosis.
Bulbar VKC commonly occurs in dark-skinned individuals.
- Papillae: Multiple, small, nodule-like papillae occur at the limbus (junction between cornea and conjunctiva), mostly at the upper part and have a thick gelatinous appearance.
- Horner-Trantas dots: Horner-Trantas dots (collections of degenerated epithelial cells and eosinophils) appear as multiple yellow-white spots at the apices of limbal papillae. Horner-Trantas dots rarely last longer than a week from their initial presentation.
- Micropannus: Micropannus is a superficial fibrovascular proliferation that extends 1-2 mm beyond normal vascular arcade. Micropannus may develop, more commonly, around upper limbus. (Roy Frederick Hampton, Fraunfelder Frederick W., Fraunfelder Frederick T., Roy and Fraunfelder's Current Ocular Therapy. Sixth Edition. Saunders Elsevier. 2008. P.366.)
- Chronic limbitis (inflammation): Chronic limbitis, more common in black patients, is characterised by hyperaemic, oedematous and thickened conjunctiva. In severe cases, chronic limbitis may cause 360 degrees limbal cell deficiency.
- Peri-limbal conjunctival pigmentation: Patients may develop typical peri-limbal conjunctival pigmentation. Extent of pigmentation does not correlate with the severity of symptoms and signs of VKC. Pigment may persist when the disease becomes inactive.
Mixed VKC shows features of both palpebral and bulbar forms.
While corneal vascularisation is rare (late corneal vascularisation may take place), cornea may be affected in a variety of ways, such as:
- Punctate epithelial keratopathy (PEK): Punctate epithelial keratopathy (PEK) may result from toxic effect of inflammatory mediators. PEK can coalesce, resulting in frank epithelial erosion or shield ulcer.
- Epithelial erosions: PEK may coalesce and form epithelial erosions.
- Shield Ulcer: Shield ulcers are oval-shaped epithelial defects and usually have their lower border in upper half of visual axis. Pathogenesis of shield ulcer is not well understood, major factor for its development may be chronic mechanical irritation from giant palpebral papillae. Healed shield ulcers may leave a sub-epithelial ring-like scar.
- Vernal pseudogerontoxon: Vernal pseudogerontoxon, with appearance of ‘Cupid’s Bow’ (outline in a previously inflamed segment of the limbus), is a degenerative lesion in peripheral cornea resembling arcus (white ring in periphery of cornea) senilis. Pseudogerontoxon is a waxing and waning grey-white lipid deposition in superficial stroma of peripheral cornea.
- Plaque formation: Plaque is usually caused by epithelial erosions in which the bare area becomes coated with fibrin and layers of desiccated mucus. Plaque resists wetting by tears and re-epithelialisation. New vessel growth may occur in plaque.
- Sub-epithelial scarring: Sub-epithelial scarring, usually in the form of a ring, is a sign of previous severe corneal involvement.
- Keratoconus: Keratoconus may be seen in chronic cases, which may be associated with chronic eye rubbing.
The skin of the eyelid and eyelid margin is relatively uninvolved. Conjunctiva of the fornices (junction between palpebral and bulbar conjunctiva) usually does not show shortening and symblepharon (adhesion between palpebral and bulbar conjunctiva) formation is uncommon. Iritis (inflammation of iris) is not reported in VKC.
No precise diagnostic criteria, is established for VKC. Hyperaemia, itching, watering, photophobia and thick mucoid discharge are typical features of VKC. Large papillae on upper palpebral conjunctiva and corneo-scleral junction are hallmarks of VKC.
Histopathology and immunohistochemistry:
Histopathology of conjunctival tissue shows a prominent inflammatory cellular infiltration in epithelium and substantia propria and post-inflammatory tissue remodelling. Tissue remodelling is more marked in palpebral rather than bulbar conjunctiva.
Tissue inflammation in chronic cases shows cellular infiltration of both stroma and epithelium, particularly in specimens taken from limbus. Cellular infiltrates consist of eosinophils, mast cells, basophils, macrophages, plasma cells and B-lymphocytes, frequently organised as small lymphoid follicles without germinal center. Eosinophils are characteristic constituents of cellular infiltrates.
In palpebral conjunctiva, stromal infiltrate consists of diffuse T-lymphocyte reaction with clustering of B-lymphocytes, eosinophils, plasma cells and mast cells.
Overgrowth of conjunctival connective tissue, with formation of large and sessile papillae on upper palpebral conjunctiva, is one of the most notable finding. Conjunctival thickening, subepithelial fibrosis, neovascularisation and scarring are typical in chronic cases. Epithelial changes, connective tissue deposition, cellular infiltration, oedema and glandular hypertrophy contribute in tissue remodelling.
On histological examination, number of goblet cells is increased in giant papillae and epithelial in-growth. Epithelial in-growth in stroma is rich in goblet cells and may give pseudo-glandular appearance. Collagen fibers in palpebral giant papilla are thicker, increased and irregularly arranged. A proliferation of capillaries and neo-vascular formations provide vascular support to the papillae. Various growth factors are increased in VKC as compared to normal subjects.
Mediators in VKC:
Number of mediators and cytokines in chronic inflammatory VKC occur on ocular surface:
- Cytokines: Cytokines are small secreted proteins that mediate and regulate immunity and inflammation. These are not stored in body, but have to be produced in response to a stimulus.
- Chemokines: Chemokines are multi-potent cytokines which localise and enhance inflammation by inducing chemotaxis and cell activation of different inflammatory cells present at sites of inflammation.
- Histamine: Histamine is an important inflammatory mediator in allergic eye disease and is released by activated mast cells and basophils. Skin test reactivity to histamine shows a greater wheal and flare response in patients with VKC, suggesting hypersensitivity. Histamine causes pruritus (itching), hyperaemia and participates in allergic inflammation and tissue remodelling by altering behaviour of conjuctival epithelium and fibroblasts.
- Metalloproteinases (MMPs): Metalloproteinases (MMPs) are extracellular endopeptidases that selectively degrade components of extracellular matrix. Increased production and activation of MMPs is probably involved in the pathogenesis of conjunctival inflammation, remodelling and corneal changes.
- Growth factors: Several growth factors, such as epidermal growth factor, fibroblast growth factor and transforming growth factor are increased in VKC. These factors induce fibroblast growth and pro-collagen production.
Cells in VKC:
Mast cells, eosinophils, T-lymphocytes, and natural killer cells are seen in increased number in VKC.
- Mast cells: Mast cells play a key role in initiating inflammatory cascade. Mast cells are the constant feature of conjunctival tissue in patients of VKC. Increased number of mast cells in palpebral giant cells suggests an active role for these cells in abnormal connective tissue metabolism observed in VKC.
- Eosinophils: Eosinophils are the constant feature seen in lacrimal and conjunctival cytology. Majority of cells in tears during active phase of VKC are eosinophils. Eosinophils and mast cells are the main effector cells in ocular inflammation in VKC.
- T-lymphocytes: T-lymphocytes increase in conjunctiva of patients with VKC. T-lymphocytes play a vital role in the pathogenesis of chronic allergic inflammation.
- B-lymphocytes: B-lymphocytes are responsible for IgE.
- Natural killer cells: Increased Natural killer cells in conjunctiva suggests a potential role of these cells and innate immunity in VKC.
- Epithelial cells: Epithelial cells act as mechanical barrier and participate in regulation of allergic inflammation.
- Fibroblasts: Fibroblasts, maintains tissue structure, contribute to the induction and amplification of ocular allergic inflammation and tissue remodelling.
VKC should be differentiated from:
- Atopic keratoconjunctivitis.
- Giant papillary conjunctivitis.
- Superior limbic keratoconjunctivitis.
- Bacterial conjunctivitis.
- Viral conjunctivitia.
Management should be carried out under medical supervision.
Education of patients and their parents about the chronic, recurrent and ultimately resolving nature of disease is an important aspect of management. Compliance with medical advice is better with a well-informed patient.
- Avoid non-specific triggering stimuli: Avoid non-specific triggering stimuli such as exposure to wind, sun and salt water which causes frequent conjunctival redness.
- Avoid allergens: Contact with common allergens like plants and flowers should be avoided.
- Sunglasses: Use of protective sunglasses is helpful and should be advised.
- Artificial tears: Artificial tears have been shown to be effective in relief of symptoms by direct removal and dilution of allergens from the ocular surface.
- Cold compresses: cold compresses provide symptomatic relief, especially from ocular pruritus.
- Frequent washing: Frequent face, hand and hair washing, especially before going to bed, may be helpful.
Most drugs used are merely palliative, and are not enough to treat and eliminate allergic ocular inflammation, so there is recurrence of disease on discontinuation of therapy.
Judicious and scrupulous use of medicines is important because drug treatment is prolonged and frequent. Some patients may need medicine throughout the year for satisfactory symptomatic relief.
Drugs to treat VKC include:
Variety of currently available drugs to treat VKC includes vasoconstrictors, anti-histamines, mast-cell stabiliser, dual-action drugs, non-steroidal anti-inflammatory drugs, corticosteroids, immunomodulators and anti-metabolites.
- Topical vasoconstrictor and non-specific anti-histamines: Topical vasoconstrictor and non-specific anti-histamine combination eye-drops are being used for long and are safe and effective, at least temporarily. Being available over the counter, these are tried by many patients during early stage of disease. These medicines relieve itching and reduce redness of eyes. There may be burning or stinging on instillation and rebound hyperaemia on discontinuation. This group contain vasoconstrictors like naphazoline or tetrahydrozoline and anti-histamines like pyrilamine and pheniramine.
- Systemic anti-histamines: Systemic oral anti-histamines may be used when allergy involves the eyes, pharynx and nose simultaneously. For allergic complaints limited to eyes, topical anti-histamines are prescribed and are free of untoward side-effects of systemic oral anti-histamines. Topical anti-histamines provide faster relief than systemic anti-histamines and have longer duration of action than topical vasoconstrictors, non-steroidal anti-inflammatory drugs, pure mast cell stabilisers and corticosteroids, the drugs commonly used in the treatment of ocular allergy.
- Topical mast-cell stabilisers: Topical mast-cell stabilisers prevent mast-cell degranulation or antagonise the effects of primary mediator histamine, being released by mast cells. Drug modulation of mast cell activity alleviates acute symptoms of active disease and reduces development of chronic allergic inflammation. These medicines may be used at the onset of allergic season and continued throughout the season. This group contain drugs like sodium cromoglycate, lodoxamide, nedocromil and pemirolast.
- Topical selective H1 receptor blockers: Topical selective H1 receptor blockers are better than vasoconstrictors alone or in combination with non-specific anti-histamine eye-drops, in controlling signs and symptoms of VKC. The group contains drugs like emedastine and levocabastine. The enhanced clinical efficacy of these medicines over first-generation anti-histamines like pheniramine may be due to inhibitory effects of new-generation anti-histamines on the pro-inflammatory cytokines.
- H1 receptor blocker and mast-cell stabiliser (dual action drugs): New generation of drugs show dual activity of H1 receptor antagonism and mast-cell stabilising property. Drugs in this group are olopatadine, epinastine, azelastine and ketotifen. These drugs also exert anti-inflammatory effects through other mechanisms e.g. olopatadine affects release of cytokines and ketotifen prevents eosinophil accumulation.
- Topical non-steroidal anti-inflammatory drugs (NSAIDs): Topical non-steroidal anti-inflammatory drugs diminish ocular pruritus and conjunctival redness associated with allergic conjunctivitis. Drugs in this group are ketorolac and diclofenac. These medicines inhibit pruritogenic prostaglandin production, and are good alternative to corticosteroids.
- Topical corticosteroids: Topical corticosteroids are one of the most effective medicines to control symptoms of VKC. These should not be prescribed as first-line treatment due to associated complications with their prolonged use viz. Steroid-induced cataract, glaucoma and susceptibility to viral and fungal infections. Modified steroids such as loteprednol etabonate and rimexolone may be used, and loteprednol has superior safety profile.
Although corticosteroids are the most efficacious medicines, steroid-resistant forms of VKC are not unusual and may necessitate alternative treatment.
- Immunomodulators: Immunomodulators like cyclosporine, a fungal metabolite, decreases signs and symptoms of VKC. However, symptoms may recur after discontinuation of cyclosporine eye-drops. Topical corticosteroids and artificial tears have been shown to act synergistically with cyclosporine eye-drops and help in re-epithelialisation of corticosteroid-resistant shield ulcers.
- Anti-metabolites: Anti-metabolites like Mitomycin-C (MMC) is an inhibitor of fibroblast proliferation. MMC decreases mucoid discharge, conjunctival hyperaemia and limbal oedema in patients who are refractory to topical steroids and mast-cell stabilisers.
Following surgical measures may be taken:
- Excision of giant papillae: Surgical excision of giant papillae is recommended if they cause lesions on the cornea. Excision of large papillae helps in early resolution of corneal epitheliopathy or ulcer, although papillae may regrow. Intra-operative application of MMC to upper palpebral conjunctiva immediately after papillae resection significantly reduces the chances of recurrence of papillae.
- Cryotherapy: Like excision of papillae, cryocoagulation may also helps in resolution of corneal epitheliopathy or ulcer. Cryotherapy of giant papillae leads to inflammation and may cause conjunctival scarring.
- Carbon dioxide (CO2) laser: Carbon dioxide (CO2) laser may be used to remove giant papillae. This procedure may be repeated on recurrence of papillae.
- Debridement of ulcer base: Debridement of ulcer base may promote re-epithelialisation.
- Removal of plaque: Surgical removal of plaque may also promote re-epithelialisation.
- Excimer laser photo-therapeutic keratectomy (PTK): Excimer laser photo-therapeutic keratectomy (PTK) helps in early re-epithelialisation of vernal shield ulcer refractory to medical treatment.
- Free autologous (derived from self) conjunctival graft: Free autologous conjunctival graft after resection of giant papillae facilitates re-epithelialisation of non-healing shield ulcer.
- Amniotic membrane graft: Amniotic membrane graft leads to complete re-epithelialisation of persistent corneal epithelial defects and vernal plaques, not improving by conventional medical treatment.
- Cultivated corneal epithelial cells: Cultivated corneal epithelial cells may be transplanted to treat severe ocular surface disease. There is significant improvement in vision after transplant. Corneal epithelial cell transplant is beneficial when amniotic membrane graft is not sufficient to restore ocular surface.
In general, VKC is rather a benign and self-limiting disease that resolves with age or spontaneously at puberty. However, active disease is debilitating and necessitates therapy to contol signs and symptoms. In some patients, symptoms may persist beyond puberty into adulthood.
VKC may lead to significant vision affecting corneal complications such as scarring, ulceration and opacification. Lid involvement may significantly compromise contact lens tolerance.
Medications used for the disease may lead to complications such as preservative toxicity and steroid-induced glaucoma (raised intra-ocular pressure) or cataract.
Ocular complications of VKC may include:
- Corneal scarring.
- Corneal ulcer.
- Corneal opacity.
- Microbial keratitis (inflammation of cornea).
- Hyperplasia of limbal tissue.
- Steroid induced cataract and glaucoma.
- Visual impairment.
- Amlyopia may be caused by corneal opacity, irregular corneal astigmatism or keratoconus.
-Glaucoma or cataract may be caused by unsupervised use of topical corticosteroids.
Like most type I hypersensitivity disorders, avoidance of allergen is emphasised in prevention of disease. Although permanent relocation to a cooler climate may not be feasible in many cases, it remains a very effective relief for VKC patients.
Maintenance of an air-conditioned environment and control of dust particles may also be beneficial.