Clinics in Dermatology (2014) 32, 131–140

Periorbital (eyelid) dermatides Ronni Wolf, MD a,⁎, Edith Orion, MD b , Yalçın Tüzün, MD c a

Dermatology Unit, Kaplan Medical Center, Rehovot, Israel; School of Medicine, Hebrew University and Hadassah Medical Center, Jerusalem, Israel b Dermatology Department and Psychodermatology Clinic, Sourasky Medical Center, Tel Aviv, Israel c Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, Turkey

Abstract Physicians in various specialties—and dermatologists in particular—frequently encounter various forms of inflammation of the eyelids and of the anterior surface of the eye. Distinguishing the cause of itchy, painful, red, edematous eyelids is often difficult. Because the uppermost layer of the eyelids is part of the skin that wraps the entire body, almost every skin disease in the textbook can affect the periorbital area as well. In this contribution, we focused on the most common such disorders that require special consideration, as a result of their special appearance, their challenging diagnosis, or the nature of their treatment. We reviewed the key features of several common dermatides that affect the eyelids, such as atopic dermatitis, seborrheic dermatitis, allergic contact dermatitis, airborne contact dermatitis, rosacea, psoriasis, and others. We focused on the special clinical features, causes, and treatments specific to the delicate skin of the eyelids. Because structures of the eye itself (ie, the conjunctiva, the cornea, the lens, and the retina) may be involved in some of the discussed periorbital skin diseases, we found it useful to add a brief summary of the eyelid complications of those diseases. We then briefly reviewed some acute sightthreatening and even life-threatening infections of the eyelids, although dermatologists are not likely to be the primary care physicians responsible for treating them. © 2014 Elsevier Inc. All rights reserved.

Cicero (106-43 BCE) is credited with saying "The eyes are the mirror of the soul," and many others, including Shakespeare and Leonardo da Vinci, have echoed those sentiments. For dermatologists, the eyes—or, more specifically, the eyelids—are a transition area between the thinnest skin of the body and the conjunctiva that actually covers the eye. We consider the eyelids to be the most vulnerable and sensitive areas of the body as well as the areas with the greatest environmental and cosmetic exposure. Because the uppermost layer of the eyelids are part of the skin that wraps our entire body, almost every skin disease in the textbook can affect the periorbital area as well. In this contribution, we will focus on the most common such disorders that require special consideration, as a result of their special appearance, their challenging diagnosis, or the nature of their treatment. ⁎ Corresponding author. Fax: + 972 9 9560978. E-mail address: [email protected] (R. Wolf). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.05.035

We will also mention some less common disorders to raise the level of awareness that surrounds them because of their potential risk of serious sequelae to the patient. The range of differential diagnoses of eyelid dermatides is extensive, including as it does such conditions as eyelid inflammation, erythema, edema, weeping, and scaling, which are often accompanied by burning or itching. Distinguishing the cause of pruritic and inflamed periorbital skin may be challenging, and choosing the appropriate therapy will be as well. We will review the key features of several common dermatoses in the hope of assisting physicians with diagnosing and treating these conditions.

Eyelid dermatitis Periorbital dermatitis may be multifactorial in origin. It may be a manifestation of endogenic diseases (eg, atopic

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dermatitis [AD], seborrheic dermatitis) or the result of external exposure (ie, allergic contact dermatitis [ACD] or irritant contact dermatitis [CD], protein CD, airborne CD, photoallergic or phototoxic dermatitis, or others). A number of studies have been conducted to determine the frequency of various skin disorders that cause eyelid dermatitis.1–10 We summarized the studies that evaluated at least 100 patients (Table 1). Although their results varied considerably, they were in agreement that ACD was the most frequent cause of perioral dermatitis, with results that ranged from 30% to as high as 77%.6 The two largest series put the figure at around 30%.3,5 AD was the second most frequent cause and affected more than 10% of the evaluated patients, and this was followed by irritant CD and seborrheic dermatitis. One consistent finding among all studies was female predominance, with most reports noting that more than 90% of the patients were women, making it safe to assume that the ACD could be attributed to the use of cosmetics. It should be noted that the sample in almost all of the studies was drawn from patients who were referred to special clinics for patch testing. This means that these individuals may not be representative of the general population and that ACD may be overrepresented, because patients who present with obvious rosacea, psoriasis, seborrheic dermatitis, or other easily diagnosed conditions are not likely to be seen in a CD clinic.

Contact dermatitis CD is the most common cutaneous eruption of the eyelids (Figures 1 and 2). The eyelids are vulnerable to CD for a number of reasons. The first is their very thin skin, which allows for the easier penetration of both contact and airborne allergens. Other reasons are their unprotected location, their subsequent exposure to airborne irritants and allergens, their tendency to be touched frequently, and their being the site for the use of many cosmetics, eye care products, and eye medications. Specifically, the three major causes of eyelid CD are cosmetics, topical ophthalmic medications, and

Table 1

Fig. 1 Contact dermatitis in response to Kathon CG in a shampoo.

contact lens solutions. Paradoxically, the most common causes of ACD of the periorbital areas are cosmetics that have been applied to areas other than the eyelids themselves (ie, the hair, face, or fingernails).11,12 This form of dermatitis has been called ectopic dermatitis or ectopic CD, and it is important to bear in mind that the sites of application of the sensitizing agents are often not themselves affected. This particularly applies to hair dye and nail polish. Likewise, allergic and irritant reactions to face creams, makeup, and blushers may also be limited to the eyelids.

How often are the eyelids affected and by what products? A modest report published 25 years ago that came from a private practice in a medium-sized town in the Netherlands that analyzed 75 patients with allergies to cosmetic products (out of 1781 patients who were tested for CD) provides some answers to our questions.13 The most frequently affected sites were the face and the periorbital area (69.3%), followed by the arms (20%), hands, trunk, and axillae. The eyelids alone were affected in 18.7% of the patients, and the face together with the eyelids were affected in 40.0% of patients. Skin care products (eg, moisturizing and cleansing creams, lotions, and milks) accounted for more than half (52.3%) of the cases, followed by nail cosmetics and shaving preparations (8% each), hair cosmetics (ie, shampoo, hair color, hair dressing) and deodorants (6.8% each). Eye cosmetics (ie,

The frequency of various skin disorders that cause eyelid dermatitis

Reference

Year of Publication

No. of Patients

Allergic Contact Dermatitis

1 2 3 4 5 6 7 8 9 10

2010 2009 2008 2006 2004 2004 2003 2002 2000 1992

266 401 2035 105 1641 215 444 203 232 150

50.8% 69% 31.6% 43.8% 36% 77% 50.2% 74% 28.9% 65.3%

Irritant Contact Dermatitis 0.8% 7.6% 7.6% 10.6% 20.9% 1% 5.2% 16.6%

Atopic Dermatitis

Seborrheic Dermatitis

26.3% 11% 14.1% 2.9% 19.8% 17% 13.5% 11.3% 15.5% 14%

1.4% 18% 0.9% 36.2% 1.4% 16% 6.3% 5.4% 20.7% 4%

Periorbital (eyelid) dermatides

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Adverse reactions to ophthalmic drugs and contact lens solutions

Fig. 2

Phytocontact dermatitis.

mascara, eyeliner, eye shadow) and lip cosmetics each caused of 4.5% of the reactions. It should be noted, however, that these numbers reflect the frequency of allergic reactions detected anywhere on the body and that there were no data specific to the face or the eyelids. The author summarized studies from the United States,12,14 Spain,15 France,16 and Sweden,17 in which most ranked skin care products first and hair cosmetics (including hair coloring) second. A Swedish study of 41 cases of CD caused by cosmetics, however, ranked eyelid makeup (ie, mascara and eyeliner) first, affecting 22.9% of the reported patients.17 Here again, the reports described general reactions to cosmetics and not only to those responsible for eyelid dermatitis. Later studies18–22 and reviews21,23 confirmed these data in principle by finding that most of the allergies occur on the face and periorbital areas and that skin care products are the main culprits. What are the allergens associated with eyelid dermatitis? An analysis of data collected from patients with pure eyelid dermatitis by the North American Contact Dermatitis Group showed that the top five allergens were gold sodium thiosulfate (8.2%), fragrance mix (7.1%), balsam of Peru (6.3%), nickel sulfate (6.0%), and neomycin (3.3%).24 The most common allergens in other series were nickel, fragrance, quaternium, neomycin, and Kathon CG.1,3–5,9,10 One possible association between nickel allergy and eyelid dermatitis has been suggested as being a result of the nickel content of all pigmented makeup products, such as mascara, eye shadow, eyeliner pencil, and so on. A recent Danish study addressed this issue by comparing the frequency of nickel allergy among women with self-reported cosmetic dermatitis from the use of mascara or eye shadow with the rate seen among women without a similar history.25 Those authors found no association between having an allergy to nickel and suffering from cosmetic dermatitis as a result of the use of mascara or eye shadow, but they stated that “this does not exclude a causal relationship in selected cases.”25 The practical lesson from this study is that proven nickel allergy in a patient with periorbital ACD is not always sufficient to explain the patient’s condition and that both allergic and nonallergic causes should be investigated.

A great variety of topical medications are used in modern ophthalmology for diagnostic and therapeutic purposes. Adverse reactions to those substances include contact the inflammation of the skin (periocular dermatitis), the conjunctiva (conjunctivitis), or both. Those reactions can be either irritant/toxic or allergic/immunologic, and they can also be the result of the vehicle components and additives (eg, preservatives) as well as of the active drug itself. Preservatives are present in almost all ophthalmic preparations, and they comprise a common cause of cutaneous and ophthalmic reactions, most of which are toxic and result from chemical irritation that ranges from mild and temporary irritation to a severe toxic reaction. Among the main preservatives used in this setting (these were reviewed in 200926) are benzalkonium chloride (BAC), thimerosal, parabens, and chlorhexidine. BAC is considered moderately allergenic and more toxic than thimerosal, a mercurial product that is strongly allergenic. A PubMed search revealed that BAC produced irritant, inflammatory, and allergic reactions at incidences of 8%, 7%, and 7%, respectively, as compared with thimerosal, which had irritant, inflammatory, and allergic reactions at incidences of 3%, 3%, and 14%, respectively.26 In a large retrospective study that analyzed the patch-test results of 1554 patients with conjunctivitis or dermatitis of the eyelids, thimerosal ranked first among nonroutinely tested contact allergens: it had a positive reaction rate of 3% as compared with a rate of 0.3% for BAC.27 With regard to active agents, almost every compound among the very large number of drugs used topically in the eye has been reported to cause adverse reactions,28–31 including topical steroids.31 There has been an attempt to include many of the causative drugs in an ophthalmic tray.32–35 Although diagnostic testing with ophthalmic ingredients is problematic because false-negative results are extremely common, it still remains a preferred and firstline method to diagnose a suspected allergen until a better method becomes available.32

Airborne contact dermatitis Another cause of eyelid dermatitis is airborne CD. This form is caused by substances that are first released into the atmosphere and that then settle on exposed skin. The upper eyelids are particularly susceptible to airborne allergens and irritants, because such substances readily collect there. In fact, the eyelids are sometimes the only sites of reaction. The nature of airborne reactions can be irritant, allergic, photoallergic, phototoxic, and contact urticarial.36 Many allergens have been reported to cause airborne CD, including plants, natural resins, wood allergens, plastics, rubber, glues, metals, industrial and pharmaceutical chemicals, pesticides,

134 animal feed additives, agricultural dusts, and cigarette smoke. 36,37 Plants represent a very important cause, particularly the Asteraceae (Compositae) family; the monolactones and the sesquiterpene lactones contained in these plants are by far the most frequently described airborne allergens.38,39 The classical appearance of airborne CD is a dermatitis that is located on the exposed areas of the face, the “V area” of the neck, and the hands and the forearms. Unlike photodermatitis, areas protected from light are also involved, including the skin behind the ears (ie, “Wilkinson’s triangle”), the nasolabial folds, the skin under the chin, and, most importantly, the eyelids despite some protection by the eyebrows.40

Atopic dermatitis AD, hay fever, allergic asthma, and perennial allergic rhinitis comprise the family of atopic diseases. AD is a common skin condition, and its prevalence rates among children can reach up to 20%.41,42 The eyelids are commonly involved in AD, and it is the second most frequent cause of eyelid dermatitis, affecting more than 10% of the patients who have been evaluated in large studies (Table 1). Eyelid manifestations among AD patients are common, but the presentation varies. Atopic individuals often present with itchy red eyes, erythema, edema, coalescent papules, fissures, and fine scaling. Chronic rubbing may lead to the thickening and accentuation of the normal skin lines (ie, “lichenification”). There are some changes of the eyelids that are more specific to AD, but these occur among nonatopic individuals as well. These include Dennie-Morgan lines, allergic shiners, and periocular milia. Dennie-Morgan lines are symmetric prominent folds below the margin of the lower eyelids. They were described in 1948 by Morgan,43 who noted that his colleague Dennie considered these lines to be pathognomonic in most cases of allergy. We now know that, although these lines are commonly seen in atopic patients at birth, they are not pathognomonic, especially if they are associated with (and probably also caused by) lower eyelid dermatitis.44 “Allergic shiners” are the symmetric, asymptomatic, bluegray darkenings of the orbital skin seen frequently among patients with allergic rhinitis and AD.45 This phenomenon was believed to be caused by venous stasis caused by nasal congestion in patients with allergic rhinitis46; if that were the case, however, then this sign should be similarly common among patients with rhinitis of other causes. These allergic shiners are relatively common, even among healthy children, and they are probably even more common among children with nonallergic rhinitis. Like Dannie-Morgan lines, allergic shiners cannot be considered specific and accurate indications of AD.47 Milia (plural of milium) are minute epidermoid cysts that are lined with epidermis and filled with keratin. Periocular

R. Wolf et al. milia have been mentioned as another feature of atopy,48 but these lesions are both congenital and acquired in addition to being so common that they can hardly be considered features of any specific condition. Atopic eyelid dermatitis poses a management challenge because of the intense pruritus that perpetuates a repeated rubbing cycle and that results in clinical disease. Control of the pruritus is the most important goal of therapy, because mechanical injury from scratching induces proinflammatory cytokine and chemokine release, thereby leading to a vicious itch/scratch cycle that perpetuates the AD skin rash. This itch/scratch cycle must be broken. Restoring the impaired barrier function of the skin is the first basic task of therapy. Restoration of the epidermal barrier, which will decrease irritation and rubbing, calls for the use of a bland and mild emollient. When possible, the moisturizer should contain no preservatives and a minimal amount of additives. Ointments are preferable to lotions or creams for retaining skin moisture, but many atopic patients will not tolerate ointments that are too occlusive. If the pruritus is severe, cool tap water compresses that are applied for 20 to 30 minutes before the emollient is applied will help to decrease the itch and hydrate the skin, provided that the emollient is applied immediately after the compresses are removed and before the water evaporates. These measures may not suffice to treat severe flares, and low-potency, nonfluorinated topical steroids are often needed. Calcineurin inhibitors (eg, tacrolimus, pimecrolimus) are good alternatives that have proven to be effective; they have a good safety profile, and they are free from the side effects of steroids. Secondary staphylococcal infection, which commonly affects atopic eczematoid skin, should be treated vigorously with systemic or topical antibiotics.

Ocular complications of atopic dermatitis Ocular complications (eg, blepharitis, keratoconjunctivitis, keratoconus, uveitis, cataract, retinal detachment, herpes infection) among atopic patients have been known for years. Their incidence varies among series and has reached up to 25%49 and even 50%50 of patients. Although dermatologists are not the ones to diagnose or treat ocular diseases, it is important for dermatologists to be aware of this association and to know about the severity of ocular involvement, the consequences of these conditions and their sight-threatening potential, and the extent of their urgency. The spectrum of atopic eye disease encompasses seasonal allergic conjunctivitis, perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, atopic blepharoconjunctivitis, and giant papillary conjunctivitis. These conditions have been described with the general term chronic allergic conjunctivitis. Seasonal allergic conjunctivitis and perennial allergic conjunctivitis are the most common of the ocular allergic diseases, and they are seldom followed by permanent visual

Periorbital (eyelid) dermatides impairment. Of the two, seasonal allergic conjunctivitis is the more common form, representing half of all cases of allergic conjunctivitis. The onset of symptoms is seasonally related to specific circulating aeroallergens, such as grass pollen. Perennial allergic conjunctivitis persists throughout the year, although it involves seasonal exacerbations, because the causative allergens (eg, dust mites, animal dander, feathers) are always present. Symptoms of the two diseases include intense pruritus (usually the primary symptom), burning, tearing, and erythema. These symptoms are usually bilateral, although the degree of involvement may not be symmetrical. Ocular symptoms are often accompanied by rhinitis; if nasal symptoms dominate the clinical picture, the disease is classified as allergic rhinoconjunctivitis. The clinical signs, which may not always be present, include conjunctival hyperemia, variable degrees of chemosis, and lid swelling. There may be a fine papillary response on the palpebral conjunctiva, but the cornea is rarely involved. Vernal keratoconjunctivitis and atopic keratoconjunctivitis are more severe ocular diseases that also involve the cornea (the root kerato indicates this) and that can threaten vision. Vernal keratoconjunctivitis has a marked seasonal incidence, most often appearing in the spring. It occurs most frequently before puberty in individuals with an atopic background, and it generally “burns out” by the third decade of life. Symptoms of vernal keratoconjunctivitis include intense pruritus and, when the cornea in involved, photophobia, foreign body sensation, and tearing, with a thick and ropy mucoid discharge. Atopic keratoconjunctivitis typically begins during the late teens and early twenties, and it may persist until the fourth and fifth decades of life. A family history of atopy (eg, eczema, asthma) is very common, with more than 95% of patients with atopic keratoconjunctivitis also having eczema and with 87% having a history of asthma.51,52 Atopic keratoconjunctivitis presents with features that are similar to those of vernal keratoconjunctivitis, but one main difference is that patients with atopic keratoconjunctivitis exhibit more eyelid and periorbital skin involvement. Although atopic keratoconjunctivitis is considered to be more severe than vernal keratoconjunctivitis, both diseases may lead to extensive and potentially sight-threatening conjunctival and corneal scarring, anterior and posterior subcapsular cataracts, blepharoconjunctivitis, keratoconus, and herpes simplex keratitis. Giant papillary conjunctivitis has been directly linked to chronic exposure to foreign bodies, such as the continued use of contact lenses, ocular prostheses, sutures, scleral buckles, and other items. Another ocular disease associated with AD is corneal ectasias, an example of which is keratoconus. Interestingly, investigators of ophthalmology-based cohorts found a stronger link between the two than dermatology-based studies did (this was summarized in 201153), and the pathophysiologic background of this association is still unclear. An association or linkage between the genetic determinants of the two conditions is one possible

135 explanation, and eye rubbing stimulated by itching or discomfort caused by AD is another; a third explanation is a combination of both of these. The development of cataracts has been proposed as being an ocular sequela of AD.54,55 The incidence of cataract development among patients with AD has been reported at rates from 5% to 35%. The pathogenic mechanism for cataract development in patients with AD is unclear. The use of systemic or periocular topical corticosteroids has been postulated as a possible factor, but patients who have been treated in this manner are definitely not the only ones affected, and some authors even question the role of these medications entirely.54 Retinal detachment has been mentioned as another possible ocular disease associated with AD. A review of the literature revealed that there were about 130 cases reported in Japan up to 1995; this is in comparison with only a few reports from Europe and the United States for the same time period.56 According to that review,56 all of the patients had facial involvement, especially in the areas around the eyes. The authors suggested that retinal detachment may be a complication of AD per se and that it is not related to cataract surgery, although some of the reported patients had undergone cataract surgery before experiencing retinal detachment. The pathogenesis of this complication of AD is unknown, and it is still unclear why so many reported cases came from Japan as compared with the relatively few reports from other parts of the world.

Blepharitis The term blepharitis actually means “eyelid inflammation,” but it is currently used to refer to inflammation of the eyelid margins. Just as the eyelid architecture is divided into an anterior portion that contains the eyelashes (cilia)—with their associated sebaceous glands of Zeis and sweat glands of Moll—and a posterior portion with the meibomian glands, so too is the anatomic subdivision of blepharitis. Anterior blepharitis involves the inflammation of the eyelashes, the follicles, and the associated sebaceous glands, whereas posterior blepharitis involves the meibomian glands. Anterior blepharitis is usually infectious (most commonly staphylococcal) or seborrheic, whereas posterior blepharitis is commonly metabolic and associated with acne rosacea (Figure 3). Anterior blepharitis may demonstrate three characteristic patterns apart from the general inflammation, hyperemia, and telangiectasia: (1) eyelid margin debris of seborrheic dermatitis; (2) staphylococcal collarette; and (3) Demodex “sleeves.” Seborrheic dermatitis manifests itself as flaky seborrheic debris on the eyelashes, typically near the base. When this loose debris falls into the eye, it results in conjunctival irritation and red eye. Staphylococcal blepharitis manifests itself via a pathognomonic collarette, which is a

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Fig. 3

Rosacea with eyelid involvement.

fibrinous crust that is pierced by an eyelash and that resembles a piece of paper impaled upon a stick. The crust arises from the exudation of fibrin at the time of ulceration. Because the ulceration occurs in the orifice of a lash follicle, the fibrin surrounds a lash; it is then carried away from the surface as the lash grows and looks like a small collar (“collarette”), leaving a small ulceration at the eyelid margin. A Demodex folliculorum mite typically forms “sleeves” along the bases of the eyelashes. Its role in the etiology of blepharitis is still not fully clear. Posterior blepharitis is characterized by erythema and the thickening and occasional ulceration of the posterior eyelid margin. There are often dilated telangiectatic blood vessels. The meibomian gland orifices are inflamed and often plugged. Meibomian gland dysfunction (MGD) often leads to a functionally “dry eye” as a result of a lack of the normally oily sections of these glands, which keep the tear surface smooth and less susceptible to evaporation. In more severe cases, the conjunctiva and the cornea can become secondarily inflamed, which can result in various degrees of keratitis and corneal ulcerations. Common symptoms associated with blepharitis include a burning sensation, irritation, foreign body sensation, tearing, photophobia and blurred vision, all of which are characteristic of dry eye syndrome as well. It is important to distinguish between blepharitis and dry eye syndrome, because the treatment of these two conditions is different. One minor difference between the two is that clinical manifestations of blepharitis are usually worse in the morning, because the inflamed lids are in closer contact with the ocular surface during sleep. A slit-lamp examination and Schirmer’s test will provide further clues for diagnosis. Treatment for both anterior and posterior blepharitis often needs to be maintained for months to years and sometimes indefinitely. Most important of all is a long-term commitment to eyelid hygiene. The process begins with the application of warm compresses followed by the scrubbing of the margins with mild shampoo that has been diluted in water, often with the help of a cotton swab to remove all crusts and debris and to evacuate the gland openings. An antibiotic ophthalmic ointment is then applied to lid margins, and, if necessary, an ointment that includes a combination of antibiotics with low-potency steroids will be used for a short period of time. It is sometimes necessary to add courses of systemic antibiotics

such as doxycycline, minocycline, or azithromycin. Some newer medications that are used in this scenario are topical azithromycin and levofloxacin. When conventional treatments for blepharitis fail, some authors recommend examination for Demodex mites and add acaricidal therapy according to the findings.57 Various treatments have been used to control Demodex mites, such as mercury oxide 1% ointment, pilocarpine gel, sulfur ointment, camphorated oil, alcohol, povidone–iodine, ether, and others. Tea tree oil has recently gained some popularity,58 and systemic ivermectin has also been mentioned.59 A recent Cochrane analysis of the effectiveness of interventions for the treatment of chronic blepharitis yielded less promising—if not discouraging—results.60 The authors of the analysis concluded that, “[d]espite identifying 34 trials related to treatments for blepharitis, there is no strong evidence for any of the treatments in terms of curing chronic blepharitis.”60 According to that analysis, there is no evidence that any medical intervention is superior to conventional lid hygiene measures, such as the application of warm compresses and the eyelid margin washing described previously. The International Workshop on Meibomian Gland Dysfunction recently reviewed current practice and published evidence regarding treatment options for MGD and blepharitis.61 They noted that “[l]id hygiene is regarded as the mainstay of the clinical treatment of MGD. It usually consists of two components: application of heat and mechanical massage of the eyelids.”61 The logic behind this therapy is the improvement of meibomian gland secretion by melting the pathologically altered meibomian lipids. The warming can be achieved by many diverse means, including simple warm compresses and devices such as infrared or hot air sources. They also recommended lid hygiene and lid massage, and they concluded that “[l]id hygiene is widely considered an effective mainstream therapy for MGD and blepharitis, despite the lack of standardization of the technique and the uncertainty about patient compliance.”61 They also noted that “[s]tudies comparing the efficacy of the many available methods for eyelid warming are also lacking; nonetheless, given the near unanimity of support for this therapy among international experts and clinicians alike, patients should be instructed in lid-warming and hygiene and urged to remain compliant, to maintain long-term control symptoms.”61 As for topical antibiotics, the authors commented that “[t]opical antibiotics offer both opportunities and challenges …but solid evidence from randomized controlled clinical trials is lacking to conclusively guide antimicrobial management of MGD.”61 With regard to the use of systemic antibiotics, they stated that “[a]lthough the individual response of patients is variable and the protocols more empiric than evidence-based, tetracycline derivatives may be helpful for blocking the vicious-circle characteristics of dry eye disease and severe MGD.”61 It is not surprising that the authors, who are ophthalmologists, were less enthusiastic about using steroids: “It is difficult to justify…potential complications of

Periorbital (eyelid) dermatides steroids as acceptable risks to control a condition that is generally not vision threatening.”

Ocular psoriasis Although it is uncommon, psoriatic involvement of the eyelids does occur. Typical psoriatic plaques may be present on the eyelids and appear similar to psoriatic plaques found elsewhere on the skin, with sharply marginated plaques, a very distinctive deep red hue, and surmounted by a distinctive silvery scale. A more common eyelid involvement is in the form of psoriasiform blepharitis.62 Whether facial and eyelid psoriasis comprise a marker of severe psoriasis is still speculative.63 The treatment of eyelid psoriasis is challenging because of the potential side effects of topical corticosteroids in this area. One of the authors surveyed dermatologists for their opinions about the treatment of eyelid psoriasis, and their replies fell into a broad spectrum of practices.64 Some were against the use of topical steroids, and others recommended low-potency steroids, but some suggestions went as far as intralesional steroid injections. Phototherapy is another option, and tacrolimus and pimecrolimus have recently become good alternatives because of their good cutaneous and ocular safety profile.62,65 With regard to other structures of the eye, we are lucky to have a very comprehensive and dedicated recent review available, which we will summarize very briefly66: • A nonspecific conjunctivitis is the most common form of conjunctivitis with psoriasis, and it can occur with or without eyelid margin lesions. Conjunctival plaques of psoriasis have also been reported. • Corneal involvement with psoriasis is rare and usually the result of eyelid or conjunctival complications. Opacities with a histologic picture of psoriasis have been reported. • Uveitis has been reported among patients with psoriasis. One uncontrolled study that investigated ocular complications among 100 Singaporean Asian patients with psoriasis found two patients who had uveitis.67 Uveal involvement has been associated with the arthropathic form of psoriasis. In a study of 36 patients with uveitis and psoriasis, uveitis was more frequent and severe in the presence of the human leukocyte antigen B27.68 Differentiating Reiter’s syndrome from psoriatic uveitis can be difficult. • Lens abnormalities among patients with psoriasis are generally thought to be incidental findings.66

Periorbital and orbital cellulitis Periorbital and orbital cellulitis are two acute infectious diseases of the orbit that are associated with potentially

137 significant morbidity and mortality. Although dermatologists are not likely to be the primary care physicians responsible for treating these infections, it is not unreasonable to expect that these individuals may occasionally be the first physicians to examine affected patients and be the ones responsible for the initial diagnosis and for making decisions about urgent and appropriate interventions. For these reasons, we briefly discuss those diseases here.

Anterior (periorbital, preseptal) versus posterior (orbital) cellulitis The orbital septum separates the superficial eyelid from the deeper orbital structures. The septum is a thin membrane that originates from the periosteum at the arcus marginalis on the superior orbital rim and then descends inferiorly to join the levator aponeurosis superior to the tarsus. The septum lies beneath the orbicularis oculi muscle, and fat can occasionally overlay it, especially in Asians individuals. The orbital fat lies beneath the septum. Infections of the soft tissues anterior to the orbital septum are called periorbital cellulitis; and the ones posterior to it are called orbital cellulitis. Orbital and subperiorbital abscesses are obviously posterior to the septum. The orbital septum acts as an anatomic barrier to the spread of preseptal infection to orbital tissue. Periorbital (preseptal) cellulitis is more common than orbital cellulitis.69,70 It is primarily a pediatric disease, and it mostly occurs among patients who are less than 5 years old. Preseptal cellulitis usually results from direct inoculation near the eyelids as a result of trauma, insect bites, or any local infections (eg, dacryocystitis, impetigo, chalazion, hordeolum). In rare cases, it may also result from hematogenous seeding or secondary spread from adjacent structures. Orbital cellulitis can present in all age groups, but it is also seen more often among children who are around 7 years old.71,72 Most of the orbital cellulitis cases are caused by paranasal sinusitis and specifically by ethmoid sinusitis. Upper respiratory and odontogenic infections are further risk factors. Differentiation between periorbital and orbital cellulitis is of utmost importance: the latter is a much more serious condition with a much higher potential for vision loss as well as central nervous system complications, including cavernous sinus thrombosis, meningitis, abscesses, and death. Orbital cellulitis mandates urgent referral to an appropriate medical center. Both diseases can begin with an acute onset of painful unilateral erythema, swelling, warmth, and tenderness of the eyelid, accompanied by fever and malaise. The erythema and swelling associated with periorbital cellulitis may extend over the superior orbital rim to the brow, whereas this extension of erythema and swelling is not seen with orbital cellulitis. With orbital cellulitis, there is a diffuse infiltration of orbital tissues with inflammatory cells and consequently increased intraorbital pressure, which results in eyelid swelling, conjunctival chemosis, proptosis (ie, forward displacement or bulging of the eye), impairment of visual acuity, decreased ocular motility,

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ophthalmoplegia, and diplopia; all of these symptoms are absent in cases of periocular cellulitis. The mean white blood cell count, the erythrocyte sedimentation rate, and the Creactive protein levels are usually significantly higher among patients with orbital cellulitis as compared with those with periorbital cellulitis.69 The key to diagnosis is that there is involvement of only one eye; this is accompanied by fever, malaise, leukocytosis, and elevated erythrocyte sedimentation rate, which are the same signs of cellulitis seen at other locations (eg, the legs). These signs are helpful for differentiating infectious conditions from other noninfectious inflammations.

Orbital fungal infections Two acute and aggressive infections that may occasionally involve the orbit are mucormycosis and orbital aspergillosis. Both fungi are ubiquitous and common environmental organisms. They colonize the nasopharynx and the oropharynx without any clinical relevance. Invasive disease occurs almost exclusively among immunocompromised individuals. When it does occur, it usually spreads from the oropharynx, the sinuses, or the nasal mucosa and causes a severely and rapidly progressive inflammation, cellulitis, and gangrenous necrosis. The disease has a very poor prognosis, and it is associated with high morbidity, disfigurement, invalidity, and functional impairment. Necrotic devitalized tissues should be excised, and there is no choice but to balance the degree of mutilation against the life-threatening risk of this organism; this is always extremely frustrating and stressful for the treating physician.

Necrotizing fasciitis (NF) We will end our review with another severe acute infection that demands the awareness of all health care personnel and of dermatologists in particular: periorbital necrotizing fasciitis (NF), which is also known as “flesh-eating disease.” NF that involves the periorbita is a devastating infection. Potential outcomes include severe disfigurement, loss of the eye, and even death. Prompt and early recognition and diagnosis as well as the aggressive surgical debridement of the diseased skin can make the difference between losing or saving the patient’s sight and sometimes even the patient’s life. An excellent representative case was described in a systematic review of periorbital NF73: Presentation: The patient presented three consecutive times to his small town hospital with redness and localized painful swelling of left upper eyelid had received diagnoses of sty. No improvement had occurred after self-care treatment and topical antibiotics. Throughout the next days left eyelid erythema and swelling worsened markedly. He experienced generalized malaise, chills, vigor and vomiting. Thus, he was admitted

to the Emergency Department. On admission he was febrile, tachycardic and hypotensive. Neurological examination showed signs of spontaneous decerebration.

The patient received high doses of antibiotics intravenously and daily cycles of oxygen hyperbaric treatments; he underwent repeated surgical consecutive debridements, after which the infection resolved. The large skin defects were completely restored, and the visual acuity in the involved eye was preserved. What is emphasized in this fortunate case is the paucity of dermatologic symptoms at the beginning of the infection and the rapidity of the deterioration. It is our experience that too many cases of NF are misdiagnosed as non-necrotizing infections (and vice versa),74 and this has also been the experience of others. In a large case series of NF, only 14.6% of the patients were correctly diagnosed or suspected of having NF on admission.75 The majority of the patients (58.4%) were diagnosed as having cellulitis. It cannot be emphasized enough that the very early stage of NF, which is the time when we strive to make the correct diagnosis, is characterized by mild symptoms that provide no clues regarding the seriousness and grave prognosis of the disease. Because of the particular anatomic features of the eyelids, NF behaves differently there than elsewhere on the body. Skin infection becomes noticeable earlier, and necrosis of the thin eyelids occurs rapidly, so the interval between the onset of symptoms and the initiation of the appropriate treatment should be short. Keys to early diagnosis include not looking for “hard signs,” such as necrosis. Do not expect to see a severely ill patient with signs of septic shock. Patients with NF are often in apparently good health and walk into your clinic just like otherwise ordinary patients. Look for severe disproportionate pain and the typical rose-violet color of the erythema. Tenderness usually extends beyond the area of skin involvement.74 Alarming signs and symptoms that are specific for periorbital NF are similar to those of orbital cellulitis, and they include proptosis, ophthalmoplegia, impaired visual acuity, and reduced papillary response to light. The following useful data were presented in a very recent excellent systematic review of periorbital NF.73 Periocular NF was seen mainly in adults. A history of previous injury, such as a laceration or penetrating injury or an abrasion, was noted in 22% of the patients; blunt trauma had occurred in 17%, and a history of blepharoplasty or other surgical procedures was present in 11%. Although there are known risk factors (mainly related to alcoholism, diabetes, rheumatologic disease, chemotherapy, and immunosuppression), about half of the patients with reported NF had previously been healthy.

Conclusions Physicians in various specialties—and dermatologists in particular—frequently encounter various forms of inflammation of the eyelids and of the anterior surface of the eye.

Periorbital (eyelid) dermatides Distinguishing the cause of itching, painful, red, edematous eyelids is often difficult. We reviewed the key features of several common dermatoses that affect the eyelids, including AD, seborrheic dermatitis, ACD, airborne CD, rosacea, psoriasis, and others. We focused on the special clinical features, causes, and treatments specific to the delicate skin of the eyelids. Because the structures of the eye itself (ie, the conjunctiva, the cornea, the lens, and the retina) may be involved in some of the discussed periorbital skin diseases, we found it useful to add a brief summary of the eyelid complications of those diseases. We then briefly reviewed some acute sightthreatening and even life-threatening infections of the eyelids, although dermatologists are not likely to be the primary care physicians responsible for treating them. These often crippling and sometimes fatal diseases require prompt and early recognition to minimize damage and sometimes to save the patient’s vision or life. Because dermatologists may at some point in their careers be the first physicians to examine affected patients and be the ones responsible for the initial diagnosis, they should be familiar with these pathologies as well.

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