Ophthalmologic Manifestations of Atopic Dermatitis Clinical Presentation

Atopic dermatitis is a multifactorial disease with genetic and environmental skin factors. ^{[1, 2]} The strongest risk factors are genetic predisposition to poor skin barrier function and dysregulation of the immune system, which also predisposes to other atopic diseases include allergic rhinitis and asthma. ^[2] In fact, recent studies have implicated loss-of-function mutations in the barrier protein, filaggrin, and diminished expression of certain antimicrobial peptides in those with AD. ^{[1, 2]}

Other risk factors that have been proposed include environmental factors such as climate, diet, urban living (proposed to increase pollution exposure), tobacco smoke, and antibiotic use (which can alter the gut microbiome). ^[2] Lastly, psychological stress has been implicated as a possible contributor to disease development. ^[2]

As mentioned in the "Overview" section, many of the ophthalmologic manifestations of atopic dermatitis have been associated with frequent and aggressive eye rubbing behavior, which is likely itself secondary to skin irritation and pruritis from AD ^[21] .

Systemically, the most common symptoms include pruritus, erythema, and skin lesions of the antecubital and/or popliteal skin, eyelids, corners of the mouth, neck, outer canthi, or behind the ears. In infants, the eruption particularly involves the face, scalp, and extensor surfaces. In older children and adults, the neck and antecubital or popliteal areas more commonly are involved. Adult patients usually have a history of infantile disease that may require anecdotal history or contacting their caregivers from infancy. Most patients have a familial occurrence of symptoms of atopy. ^[2]

As mentioned in the "Overview" section, ophthalmologic manifestations of atopic dermatitis may include pruritic, erythematous lesions of the eyelids, keratoconus, atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), bacterial blepharoconjunctivitis, retinal detachment, cataract and glaucoma. ^[3]  These complications typically present with vision changes and/or ocular pain and discharge, and ophthalmic physical examination (as below) is necessary to identify the specific complication.

As mentioned in overview, AKC and VKC are more common in boys and VKC is usually seen in younger patients. VKC tends to recur in the spring/summer seasons, whereas AKC is not seasonal. ^[28]  

The most common physical findings are erythematous, exudative skin lesions of the antecubital and/or popliteal skin, eyelids, corners of the mouth, neck, outer canthi, or behind the ears. Cutaneous scaling, thickening of the skin secondary to irritation and scratching (i.e. lichenification), pigmentary changes including vitiligo and hyperpigmentation (especially in darker skin types), are common in adolescents and adults. ^[29]  In severe cases, generalized eruptions over the entire body may occur. ^[29]

More specific physical examination findings of specific ophthalmologic manifestations include:

- Keratoconus : KC is usually bilateral but often asymmetric, and usually presents with slowly progressive irregular astigmatism resulting from paracentral thinning and bulging of the cornea (with maximal thinning near the apex of the protrusion), vertical tension lines in the corneal endothelium (Vogt striae), epithelial iron deposits on the base of the cone (Fleischer ring), an irregular corneal retinoscopic reflex (scissor reflex), and egg-shaped Mires on keratometry. Corneal topography typically shows inferior steepening, and corneal tomography shows posterior elevation. ^[28] Late-stage KC is characterized by Munson sign (bulging of the lower eyelid when looking downwards) and superficial corneal scarring. ^[28]  

- Atopic/Vernal Keratoconjunctivitis (AKC and VKC):  ^{[30, 31]}  Typically bilateral but frequently asymmetric itching with thick, ropy discharge. ^[28]  

• AKC signs  include eyelid and periorbital skin erythema and thickened dry skin with blistered patches. The tarsal border of the eyelid is thickened (i.e. tylosis) with crusting and scaling, and the meibomian glands are typically dysfunctional. The conjunctiva is typically hyperemic and edematous, with prominent tarsal papillae (i.e. papillary conjunctivitis), which can lead to conjunctival scarring and symblepharon in severe cases. Horner-Trantas dots may be present. The cornea is usually involved, with mild disease including punctate epithelial erosions to ulceration and even perforation, as well as peripheral vascularization and pannus. Anterior and posterior subcapsular cataracts are common. ^[28]  
• VKC signs  include diffuse conjunctival injection and  upper tarsal  giant papillae (giant papillary reaction is more common with VKC than AKC) that can also be near the limbus. Perilimbal Horner-Trantas dots can form, which are focal white limbal dots consisting of degenerated epithelial cells and eosinophils. Like AKC, limbal disease can result in limbal stem cell deficiency which can lead to corneal neovascularization and pannus. Corneal signs related to VKC also include punctate epithelial erosions, which can coalesce into macro-erosions of the corneal epithelium, which in turn can accumulate fibrin and mucous, forming Shield ulcers. Corneal scarring can occur as corneal neovascularization resolves. Lastly, a gray-white lipid can deposit in the peripheral superficial corneal stroma, and is known as pseudogerontoxon. ^[28]  

- Bacterial Blepharoconjunctivitis : Dysregulation in skin barrier allows for much higher infection rate in AD patients than in normal population (67% vs 6% Staphylococcus aureus infection rate). ^[21]  Physical examination signs include purulent white-yellow discharge, conjunctival papillae, chemosis, and lack of lymphadenopathy. ^[28]  Cultures typically grow S. aureus (as mentioned in Overview section), but can also grow S. epidermidis, H. influenzae (especially in children, commonly associated with otitis media), Strep pneumoniae, and Moraxella catarrhalis. ^[28]  

- Cicatricial entropion:  describes inward turning of the eyelid margin and its appendages secondary to chronic inflammatory changes and subsequent fibrosis, scarring and shortening of the posterior lamellae, and can lead to lash-cornea touch that results in corneal abrasion, scarring, thinning, neovascularization, or even corneal ulceration and perforation. ^[11]  Cicatricial entropion is unique from other causes of entropion as it is usually secondary to a systemic inflammatory condition, such as AD, and therefore its definitive treatment should target medical control of the underlying pathologic condition when present. ^[11]  

- Cicatricial ectropion:  is caused by shortening of the anterior lamella, and is also secondary to chronic inflammatory changes including fibrosis and scarring. ^[12] Similar to other types of ectropion, cicatricial ectropion can lead to exposure keratopathy, corneal abrasion, ulceration, and even thinning and perforation. ^[12] Like cicatricial entropion, definitive therapy includes treatment of the underlying source of inflammation. 

- Retinal Detachment : AD patients develop retinal detachment in second or third decade of life, and likely to occur bilaterally, likely secondary to retinal tears in the periphery secondary eye rubbing (similar mechanism as ocular trauma). ^[21]  Exam findings of rhegmatogenous retinal detachments include elevation of the retina from the retinal pigment epithelium by fluid in the subretinal space due to an accompanying full-thickness retinal break(s), with or without anterior vitreous pigmented cells (ie, Shafer sign). ^[28]  A mild relative afferent pupillary defect may be present. ^[28]  

- Cataracts : Cataracts associated with AD are typically anterior and/or posterior subcapsular cataracts, and are distinct from the nuclear and cortical cataracts common in the general population. ^[21]  These cataracts usually develop in patients with long-standing atopic disease (ie, 10 or more years). These cataracts are typically bilateral and tend to evolve rapidly, with opacification within 6 months. The cataracts often begin as a posterior subcapsular opacity and develop into an anterior subcapsular opacity that frequently resembles the shape of a shield. ^[32]

- Atopic glaucoma:  Exam findings of "atopic glaucoma" have been proposed by Takakuwa et al. as vertical cup-disc ratio > 0.7 and/or notching of the neuroretinal rim with compatible visual field loss, intraocular pressure > 21 mmHg, with the presence of severe atopic dermatitis as defined by the Japanese Dermatological Society (i.e. rash affects face, rash involves 10-30% of body surface area in severe AD, and >30% of the body surface area in very severe AD). ^[19]  These researchers obtained aqueous humor samples to assess for inflammatory cytokine expression, but excluded patients on glucocorticoids, and also excluded any case that showed an apparent relation between glucocorticoid usage and IOP, in order to propose "atopic glaucoma" as a unique clinical diagnosis associated with intraocular inflammation secondary to severe or very severe AD. ^[19]

- Herpetic Eye Disease : AD patients have a four-fold increased risk of developing ocular Herpes Simplex Virus (HSV). ^[21]  Physical exam findings related to herpetic eye disease differ on the location and severity of disease, and may involve the eyelid/skin (i.e. clear vesicles on an erythematous base that progress to crusting), conjunctivitis (i.e. conjunctival injection with ipsilateral follicular conjunctivitis, with or without conjunctival dendrites or geographic ulceration), corneal epithelial disease (ie, dendritic keratitis, geographic ulcer, corneal desensitivity, subepithelial scars and haze in the healing stages, neurotrophic ulceration, disciform keratitis, necrotizing interstitial keratitis, herpetic uveitis, herpetic retinitis). ^[28]