Atopic keratoconjunctivitis (AKC) is a relatively uncommon, but potentially blinding ocular (eye) disease, which typically affects young people with atopic dermatitis. AKC is a severe chronic inflammatory disease of the conjunctiva which may have dramatic consequences for visual function.
Atopic keratoconjunctivitis represents a disease under chronic allergic conjunctivitis (CAC), together with seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC) and, to a certain extent, giant papillary conjunctivitis (GPC). The potential for corneal involvement and opacification increases significantly with the CACs because of the severity and sustained nature of their inflammation. In seasonal and perennial allergic conjunctivitis, conjunctival inflammation is quite mild and corneal involvement is rare. However, clinical and patho-physiological features of AKC are quite different from other allergic conjunctivitis. AKC like vernal keratoconjunctivitis, is a severe inflammatory disease, which may involve cornea and can cause permanent visual impairment. The highest incidence of visual loss is therefore, found in AKC, the most chronic of these disorders.
Unlike SAC, symptoms of AKC are usually present year-round, though a significant number of patients may have seasonal exacerbations.
Ocular symptoms of AKC:
– Moderate to severe Itching.
– Tearing of eyes.
– Burning sensation.
– Dermatitis of eyelids and peri-orbital skin.
– Peri-orbital hyper-pigmentation.
– Chronic eyelid oedema and inflammation.
– Entropion (inward turning of eyelid).
– Ptosis (drooping of upper eyelid).
– Lagophthalmos (incomplete or defective closure of eyelids).
– Madarosis (loss of eyelashes).
– Redness of eyes.
– Stringy mucoid discharge.
– Difficulty in opening the eyes on awakening.
– Discomfort in eyes.
– Photophobia (sensitivity to light).
– Blurring of vision.
Atopic keratoconjunctivitis is a chronic allergic conjunctivitis and may be due to:
All ocular allergic disorders are characterised by a hypersensitivity response, defined as an excessive reaction of the normal immune system, usually by exposure to an inciting antigen.
Type I hypersensitivity, or IgE mediated immediate hypersensitivity, predominates in PAC and SAC, but is also involved in other CACs, including AKC. Serum IgE levels are chronically elevated in AKC patients but their levels are not necessarily correlated to severity of disease. IgE levels in tear samples are also increased in AKC, and correlate with serum IgE levels.
AKC additionally involves a chronic inflammation of the ocular surface; a type IV delayed hypersensitivity response, where an immediate antigen is not easily identified.
A genetic predisposition combined with antigen sensitisation is suspected in AKC and its associated disease, atopic dermatitis. AKC may, however, represent either a common manifestation end point for a number of abnormal gene processes, or a single gene defect with variable phenotypic expression, modified by other gene polymorphisms and the environment.
Epithelial barrier defect:
More recent studies suggest that an epithelial barrier defect may be responsible rather than a defect in immune-regulatory function.
Atopic (genetic tendency to develop allergic disease) systemic diseases with which AKC may be associated are:
– Dermatitis is most common.
– Hay Fever.
– Urticaria (hives).
– Food allergies (less common).
– Non-hereditary angioedema (less common).
AKC may be associated with other ocular diseases like:
– Anterior sub-capsular cataract.
– Posterior sub-capsular cataract.
– Chronic staphylococcal blepharitis.
– Retinal detachment.
Diagnosis of AKC is based upon typical clinical features.
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 AKC.
Ocular clinical features:
– Dermatitis: Scaling, flaky dermatitis consistent with eczema on peri-orbital skin.
– Hyperpigmentation: Peri-orbital hyper-pigmentation, which may lighten in response to control of inflammation.
– de Hertoghe sign: de Hertoghe sign or absence of lateral eyebrow, is occasionally seen and may be related to chronic eye rubbing.
– Dermatitis: Scaling, flaky dermatitis with reddened base, consistent with eczema on eyelids.
– Vertical corrugations: Vertical corrugations near medial canthus of upper and lower eyelid may result.
– Fissured eyelid skin: Eyelid skin is often fissured.
– Eyelid margin thickening: Eyelid margins may be thickened, oedematous and hyperaemic.
– Dennie-Morgan lines: Eyelid oedema may lead to Dennie-Morgan lines, single or double creases in the lower eyelid, secondary to chronic eye rubbing.
– Lateral canthal ulceration: Lateral canthal ulceration related to chronic tearing may be present.
– Lid mal-position: Lid mal-position may result from chronic eyelid oedema and inflammation, resulting into:
1. Ectropion (outward turning of eyelid).
3. Lagophthalmos may result from chronic eyelid oedema and inflammation.
– Madarosis: Madarosis may also result from chronic eyelid oedema and inflammation. Lid margins may show loss of cilia and punctal ectropion.
– Permanent lid swelling: Chronic oedema may lead to permanent lid swelling, a hallmark of long-standing atopic eye disease.
– Eyelid margin keratinisation: Keratinisation of eyelid margins is sometimes observed, along with associated meibomitis (inflammation of meibomian glands) and obliteration of meibomian glands.
– Palpebral conjunctiva: Palpebral conjunctiva shows papillary hypertrophy, more prominent on lower tarsus.
– Giant papillae: Giant papillae like VKC may form.
– Oedema: Diffuse sheet-like infiltration of conjunctiva may lead to pale white oedema and obscuration of blood vessels. Bulbar conjunctiva typically displays diffuse chemosis and injection.
– Conjuctival scarring: Conjuctival scarring may occur, often in reticular or septal pattern.
– Symblepharon (adhesion between palpebral and bulbar conjunctiva) formation: Sub-epithelial fibrosis can, in severe cases, lead to symblepharon formation.
– Forniceal foreshortening: Forniceal foreshortening may also result from sub-epithelial fibrosis.
– Limbus: Limbus may become infiltrated and oedematous, and develop gelatinous limbal thickening, consisting of confluent macro-papillae, is sometimes seen.
– Trantas dots: Trantas dots, tiny white lesions consisting of necrotic epithelial cells and eosinophils, may be observed, similar to those in VKC.
Corneal disease may be complicated by late development of corneal hypaesthesia in patients with AKC, resulting in a paradoxic reduction in surface symptoms, including itching.
– Punctate epithelial keratopathy: Punctate epithelial keratopathy is the most common corneal finding.
– Filamentary keratitis: Filamentary keratitis may occur, sometimes with very thick mucoid filamentary strands and possibly related to tear film instability, due to goblet cell abnormalities and deficient mucin secretion, also commonly featured in AKC.
– Persistent epithelial defects: Persistent epithelial defects frequently occur in the setting of a dry and inflamed ocular surface and may eventually lead to macro-erosions. Macro-erosions in atopic patient may progress to frank bacterial ulcers.
– Atopic shield ulcers with ‘vernal’ plaque formation: Atopic shield ulcers with ‘vernal’ plaque formation may also develop. Adherent mucus plaques contain epithelial debris, eosinophils, and inflammatory cells, and probably result from a combination of mechanical irritation from giant papillae, as well as toxic epithelial changes secondary to inflammation. Persistence of these plaques may eventually cause stromal thinning and perforation. The chronic inflammation and mechanical insult from palpebral scarring may result in partial or total limbal stem cell deficiency. Chronic inflammation and superimposed infection may lead to corneal scarring, neovascularisation, and lipid deposition. Vision may decline due to obscuration of the visual axis, irregular astigmatism, and/or ocular surface compromise.
– Pannus formation: Severe pannus often develops, typically affecting the superior one-third of the cornea.
– Pseudogerontoxon: Pseudogerontoxon may be seen in the peripheral cornea, which resembles a short, circumferential segment of arcus-senilis (white or grey opaque ring in corneal margin). This localised area of lipid deposition, related to abnormal vascular permeability at the limbus, may be the only evidence of previous atopic disease in a quiet eye.
– Eyelid inflammation: Eyelid inflammation is common in AKC, often related to staphylococcal blepharitis. Patients with atopic dermatitis are found to have high rates of bacterial skin colonisation, specifically with staphylococcal species.
– Corneal super-infections: AKC patients are at higher risk of corneal super-infections because of an unstable ocular surface, the local bacterial colonisation of the eyelids, and a dysfunctional innate immune system. Herpes simplex virus (HSV) keratitis, frequently bilateral, is another well known complication of AKC, and is presumably related to abnormalities in the atopic host’s immune defences. Herpetic epithelial lesions may be recurrent, especially when topical or systemic immune-suppressants are required to control the atopic state. Management is especially difficult because epithelial AKC lesions may be difficult to distinguish from HSV keratitis.
– Development of cataract: Rapidly progressive cataracts frequently develop in AKC patients, classically described as anterior sub-capsular opacities, usually stellate or shield like in appearance. The pathogenesis for atopic cataract is unclear, and it is suggested that high levels of IgE may be correlated with development of cataract in these patients. The chronic use of topical steroids also predisposes to posterior sub-capsular cataracts in AKC patients. Other forms of cataract may form independent of corticosteroid use, especially in patients with severe systemic atopic disease.
– Keratoconus: A higher incidence of keratoconus is reported in AKC, likely related in part to chronic eye rubbing.
– Pellucid marginal degeneration: A higher incidence of pellucid marginal degeneration is reported in AKC, likely related in part to chronic eye rubbing.
– Retinal detachment: Slightly higher rate of retinal detachment has also been noted in AKC patients. This may also be related to chronic eye rubbing, inducing degenerative vitreous changes.
Histological/ Immuno-histochemical studies:
Histological/ Immuno-histochemical studies of conjunctival specimens reveal increased number of mast cells, eosinophils, T lymphocytes and neutrophils in AKC patients.
Mast cells and eosinophils have not only been detected in conjunctival epithelium, but are also present in increased numbers in the substantia propria. A surplus of Langerhans cells, macrophages and B cells in the substantia propria is also seen.
T-lymphocyte infiltration is apparent in both conjunctival epithelium and substantia propria in AKC. T-helper (Th) cells predominate in all allergic eye diseases. Of the major T-cell subtypes, the Th1 subtype is involved in cellular immunity, whereas Th2 subtype is involved in humoral immune responses, including those mediated by IgE. Th2 cells are involved in eosinophil recruitment and stimulate IgE production from B cells. Th2 cytokines are involved in the recruitment and activation of inflammatory cells in AKC.
Activated eosinophils recruit additional inflammatory cells to the ocular surface. They release chemo-attractants which attract neutrophils to the conjunctiva. Eosinophils are also major players in the development of sight-threatening corneal complications in AKC.
Conjunctival Epithelial cells and Fibroblasts express pro-inflammatory mediators in VKC. The expression of surface adhesion molecules and the release of cytokines by epithelial cells enhance recruitment of eosinophils. Conjunctival fibroblasts, when activated by Th cytokines, promote local accumulation of eosinophils and enhance eosinophil degranulation.
Secondary structural changes:
Extensive inflammation in AKC leads to chronic ocular surface alterations:
– Goblet cell loss/hyperplasia: Both goblet cell loss (based on impression cytology), as well as goblet cell hyperplasia (based on conjunctival biopsy) have been reported. Goblet cell production of mucin is altered.
– Tear film instability: Tear film instability, with increased tear break-up time (BUT) but normal tear production, has also been described.
– Corneal sensation: Corneal sensations are reduced in AKC..
–Squamous metaplasia: Squamous metaplasia has also been described in patients with AKC.
Confocal microscopy studies:
AKC is associated with alterations in basal epithelium and sub-basal corneal nerves which relate to changes in tear function and corneal sensitivity. There is lower density of basal epithelial cells. A decrease in number and density of sub-basal long nerve fibers causes decreased corneal sensation. Corneal nerves are thickened and have bifurcation abnormalities. Inflammatory cells and activated keratocytes are found in the superficial stroma.
AKC should be differentiated from:
– Chronic allergic conjunctivitis (e.g. VKC).
– Viral conjunctivitis.
– Cicatricial pemphigoid.
Similarities and differentiation from VKC:
– Potentially blinding chronic disease: AKC and VKC are chronic, potentially blinding conditions.
– Atopy: Both conditions present in individuals predisposed by an atopic background.
– Hypersensitivity responses: Both diseases involve both type I and type IV hypersensitivity responses. Eosinophils and T lymphocytes are found to infiltrate the conjunctiva in both conditions.
– Clinical features: Clinically, they are similar, with conjunctival inflammation, epithelial defects, shield ulcers, and corneal scarring as major features of both.
– Age groups: AKC presents at an older age than VKC. VKC usually ‘burns out’ by late puberty, whereas AKC remains chronic for years, often persisting into old age, when it may resolve spontaneously.
– Visual prognosis: Visual prognosis is worse for AKC.
– Peri-orbital skin and eyelid: There is increased peri-orbital and eyelid skin involvement in AKC as compared to VKC which generally spare skin.
– Papillae: AKC usually presents with micro-papillae on the palpebral conjunctiva. Lower tarsus is preferentially involved in AKC, in contrast to VKC, in which papillae are much more prominent on the upper tarsus. Giant papillae are sometimes seen in AKC, but this is a definitive hallmark of VKC.
– Eyelid margins: The eyelid margins are affected in AKC unlike VKC. Cicatricial changes, forniceal foreshortening, and symblepharon may be seen in AKC which are not usual in VKC.
– Trantas dots: Trantas dots are more frequently associated with VKC than AKC.
Management should be carried out under medical supervision.
Because of chronic nature of AKC, the balance of treatment efficacy and risk is often difficult. AKC is generally less responsive and requires more intensive and prolonged treatment.
The approach to management is multifaceted with the purpose of improving patient comfort and preventing the complications associated with AKC. Management involves multiple treatment arms viz. topical mast cell stabilisers, corticosteroids, steroid-sparing immunosuppressive agents such as topical cyclosporine. In more severe cases, systemic immune-suppression may be required.
– Environmental allergens: Control of environmental allergens may be helpful, but antigen avoidance is usually an adjunctive therapy.
– Eyelid hygiene: Because AKC involve the eyelids, in addition to the ocular surface, basic eyelid hygiene is essential. Eyelid scrubs should be part of daily routine in order to control blepharitis and the risk of staphylococcal keratitis. Antibiotic ointment may also be applied to the eyelid margins.
– Warm/cold compresses: Warm compresses improve tear film stability in patients with meibomian gland dysfunction related to eyelid margin inflammation.
If severe itching or an exacerbation of peri-ocular atopic dermatitis is present, cold compresses will be more likely to provide symptomatic relief.
AKC is primarily managed medically. However, elective surgery may be of benefit where inflammation is well controlled.
The goal of therapy should be the complete control of ocular surface inflammation with the safest medicines and lowest dosing needed to achieve this.
Mast cell stabilisers and antihistamines are the mainstay of prophylactic therapy. Antihistamines, steroids and immune-suppressants are used for immediate management of symptoms.
– Emollients: Emollients applied to the eyelid skin help control peri-ocular eczema.
– Steroid ointments: Mild steroid ointments also help in controlling peri-ocular eczema. As with eye-drops, the duration of treatment should be minimised and the intraocular pressure monitored.
– Immunosuppressive agent: Tacrolimus ointment, a steroid-sparing immunosuppressive agent, has also been shown to be effective in treating atopic dermatitis of the eyelids.
– Topical artificial tears: Superficial punctate keratopathy requires aggressive lubrication, with preservative-free artificial tears and lubricating ointments, with the goal of increasing comfort and avoiding frank epithelial defects, which are typically more difficult to manage in atopes.
– Topical antibiotic: If epithelial erosion does occur, topical antibiotic prophylaxis should be added to prevent bacterial super-infection and infectious keratitis, a complication of epithelial defects in AKC. All new epithelial defects should be cultured prior to initiation of broad-spectrum antibiotics.
– Bandage contact lens: Bandage contact lens may be applied to facilitate healing of the corneal epithelial defect.
– Scleral contact lenses: In patients with corneal epithelial or stromal irregularity but with good control of their AKC, scleral contact lenses may afford good vision and increased comfort, thus avoiding surgery.
– Topical acetylcysteine: Acetylcysteine, a mucolytic agent, may be used topically for dissolving mucus filaments and deposits, and addressing early plaque formation.
– Topical antihistamines: Antihistamine eye drops are prescribed for the relief of acute signs and symptoms of AKC by blocking the histamine receptors in the conjunctiva. The antihistamine is effective for the acute onset and reduces pruritus. These are generally not for continuous long term use, and several preparations are used in courses of limited duration. 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. Examples include pyrilamine and pheniramine.Topical antihistamines when used in isolation are about as effective as mast cell stabilisers. They are suitable for acute exacerbations but generally not for continuous long term use, and courses of several preparations are used in courses of limited duration.
– Systemic antihistamines: Systemic antihistamines help itching, promote sleep and reduce nocturnal eye rubbing. Because other inflammatory mediators are involved besides histamines, effectiveness is not assured. Some antihistamines (e.g.loratadine) cause relatively little drowsiness.
– Topical combined vasoconstrictor and antihistamine: Topical combined vasoconstrictor and antihistamine like antazoline (antihistamine) with xylometazoline (vasoconstrictor) may offer relief in some cases.
– Topical mast cell stabilisers: Initial management of conjunctival inflammation may involve topical mast cell stabilisers. Topical mast cell stabilisers reduce the frequency of acute exacerbations and the need for steroids and so form the basis of many regimens, but are seldom effective in isolation. Several days to weeks of treatment are needed for a reasonable response. The mast cell stabilisers include sodium cromoglycate, nedocromil, lodoxamide and pemirolast, which may be effective as maintenance therapy in mild cases of AKC.
– Topical selective second-generation H1-blocking antihistamines: 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. 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. Topical second-generation H1 antihistamines are much more selective for peripheral H1 receptors, as opposed to the central nervous system H1 receptors, cholinergic receptors, and some H2 receptors that cause cardiac arrhythmia. This selectivity significantly reduces the occurrence of adverse drug reactions, such as drowsiness/ sedative action, dry eye and dry mouth.
– Selective H1-blocking antihistamines and topical mast cell stabilisers (Dual acting drugs): Agents such as azelastine, epinastine, bepotastine, olopatadine and ketotifen have both mast cell-stabilising and anti-histamine properties, and are more frequently employed for allergic eye diseases. These agents have a relatively rapid onset of action.Although these agents have little direct effect on the T-cell mediated inflammation, they may reduce overall induction of inflammation and, importantly, reduce mechanical eye rubbing, associated with the development of keratoconus and possibly AKC-associated cataract.
– Non-steroidal anti-inflammatory preparations: Non-steroidal anti-inflammatory preparations like ketorolac and diclofenac may improve comfort by blocking non-histamine mediators. Combining one of these with a mast cell stabiliser is an effective regimen in some patients.
–Topical corticosteroid therapy: More severe inflammation in AKC usually requires topical corticosteroid therapy. Topical steroids must be prescribed only for a short period of time and for severe cases that do not respond to other therapy. Pulse dosing of topical steroids may be employed, followed by maintenance with an MC stabiliser. Modified steroids such as loteprednol etabonate and rimexolone may be used, and loteprednol has superior safety profile. Since the inflammation in AKC is on the ocular surface, corticosteroids with significant intraocular penetration should be avoided when possible. Steroid-related side effects, such as cataract and elevated intraocular pressure are often inevitable for AKC patients. Superior tarsal injection of corticosteroids is effective in refractory cases, though this treatment option may also be limited by side effects.
– Topical immune-modulator drugs: Steroid-sparing immunosuppressive drugs, such as topical cyclosporine, have immune-modulatory effect by reducing Th cells, B cells and macrophages after treatment. Side effects include intense stinging and prolonged blurred vision. Tacrolimus ointment also inhibits T-cell production with greater potency than cyclosporine.
– Systemic immune suppression: Advanced and refractory AKC may sometimes necessitate systemic immune-suppression, in order to prevent sight-threatening complications. Agents reported to be beneficial include prednisone, cyclosporine, tacrolimus, mycophenolate, and azathioprine.
The benefits of immune-suppressants, both systemic and local, must be balanced against the significant risk of infection, both bacterial and viral.
– Allergen desensitisation: Allergen desensitisation may be effective in some patients with high serum IgE levels.
– Plasmapheresis: Plasmapheresis may be done in some patients with high serum IgE levels.
– Superficial keratectomy: Shield ulcer plaques, consisting of epithelial and inflammatory debris at the base of an ulcer, often are resistant to treatment with topical anti-inflammatory therapy. Superficial keratectomy may be required to remove plaques or debride shield ulcers and allow epithelialisation. Medical treatment must be maintained until the cornea has re-epithelialised in order to prevent recurrences.
– Excimer laser phototherapeutic keratectomy (PTK): Excimer laser phototherapeutic keratectomy is an alternative to remove plaques or debride shield ulcers and allow epithelialisation.
– Penetrating keratoplasty (full-thickness corneal transplant): Corneal scarring and occasionally perforation may occur in severe cases and necessitate penetrating keratoplasty.
– Papillary resection: Papillary resection with or without mitomycin-C (MMC) application has been described as a method to reduce ocular surface inflammation.
– Surface maintenance/restoration procedures: Surface maintenance/restoration procedures may be required for severe persistent epithelial defects or ulceration. Various procedures may be:
1. Amniotic membrane overlay grafting.
2. Lamellar keratoplasty (partial-thickness corneal transplant).
3. Eyelid procedures such as botulinum toxin-induced ptosis or lateral tarsorrhaphy (surgical fusion of upper and lower eyelid margin to narrow the eyelid opening).
4. Gluing may be appropriate for focal (‘punched-out’) corneal perforations.
– Eyelid surgery: In advanced AKC, extensive scarring of the ocular surface and eyelid margins may necessitate eyelid surgery. This includes lid margin tightening and rotational procedures for lid mal-position, as well assymblepharon lysis and forniceal reconstruction for severe conjunctival scarring.
– Cataract surgery: Many patients will require cataract surgery at a relatively young age due to atopic and steroid-induced cataract development.
– Glaucoma surgery: A few patients may need glaucoma filtering surgery or valve placement if steroid-induced glaucoma develops.
– Stem cell transplantation: Patients who develop limbal stem cell deficiency may require ocular surface stem cell transplantation for visual rehabilitation.
Associated systemic conditions should be treated as well. Uncontrolled dermatitis with vision-threatening complications requires systemic steroids.
Any associated Herpes simplex keratitis should be treated with topical antiviral agents. Recurrent attacks of Herpes infection may require systemic antiviral also.
AKC remains chronic for years, often persisting into old age, when it may resolve spontaneously.
Proper prophylaxis, prompt treatment and planned surgical management can reduce the incidence of poor vision and blindness.
AKC is a potentially blinding disease. AKC may result in diminished vision or blindness from superficial punctate keratitis, persistent corneal epithelial defects, corneal scarring or thinning, cataract, keratoconus and symblepharon formation.
Patients should be observed frequently until the ocular surface disease is stable. Patients being treated with corticosteroids or immuno- suppressives, should have regular examination for drug-induced adverse effects. Corticosteroids promote the development of cataract, glaucoma and may lead to secondary corneal infections.
AKC may be associated with complications/ features like:
– Tylosis (thickening of eyelid margin).
– Staphylococcal blepharitis.
– Conjunctival fornix foreshortening.
– Recurrent herpes simplex keratitis.
– Corneal scarring.
– Corneal thinning.
– Corneal perforation.
– Pellucid marginal degeneration.
– Anterior sub-capsular cataract.
– Posterior sub-capsular cataract.
– Degenerative vitreous changes.
– Retinal detachment.
For optimal long term prevention of AKC, reduce or eliminate the exposure to environmental allergen.
Mast cell stabilisers and antihistamines are the mainstay of prophylactic therapy. Reduction of environmental allergens along with oral and topical antihistamines helps in management of exacerbations.
Hogan MJ, Atopic Keratoconjunctivitis. Trans Am Ophthalmol Soc 1952; 50: 265-81.