Table 13.1
Diagnosis of Atopic Dermatitis – Clinical Features
Essential features (must be present) | Pruritus Eczema (acute, subacute, chronic) with the typical morphology and age-specific patterns (facial, neck, and extensor involvement in infants and children; current or previous flexural lesions in any age group; sparing of the groin and axillary regions) |
Important features (seen in most cases, adding support to the diagnosis) | Early age of onset Atopy (personal or family history, IgE reactivity) Xerosis |
Associated features (help suggest the diagnosis but are too nonspecific to be used for defining or detecting atopic dermatitis) | Atypical vascular response (facial pallor, white dermographism, delayed blanch response) Keratosis pilaris Pityriasis alba Hyperlinear palms Ichthyosis Ocular and periorbital changes Perifollicular accentuation Lichenification, prurigo |
| Exclusionary conditions | Scabies Seborrheic dermatitis Irritant and contact dermatitis Cutaneous T-cell lymphoma Psoriasis Photosensitivity dermatoses Immunodeficiency diseases Erythroderma of other causes |
Periocular Manifestations
There are two clinical manifestations described in this area: periocular hyperpigmentation and Dennie-Morgan lines (a symmetric single or double prominent fold, beneath the margin of the lower eyelid) (Fig. 13.2), which are specific for AD, as they are not present in seborrheic dermatitis or contact allergic dermatitis.
Investigations
As atopic dermatitis is usually clinically diagnosed, laboratory analysis is rarely needed. Increased levels of IgE are currently the only useful measure to support the diagnosis. A bacterial skin culture can be performed if superinfection is suspected.
Different biomarkers such as eosinophilic cationic protein, total IgE, soluble IL-2 receptor, and thymus and activation-regulated chemokine have been shown to correlate with disease severity.4 Serum IL-17 and IL-23 levels are significantly higher in patients with AD than in healthy persons and patients without AD.5
Management
AD can persist for many years and requires long-term management with anti-inflammatory compounds.
Topical Treatment:
Topical application of moisturizers, containing emollients (e.g., glycol and glyceryl stearate) and humectants (e.g., glycerol, lactic acid, urea), is essential to preserve the integrity of the skin’s hydrolipidic barrier.6 The ideal agent should be safe, effective, and free of additives, fragrances, and other sensitizing agents. Consistent hydration will help prolong the intervals between outbreaks and will typically reduce the symptoms and signs. In the event of an acute flare-up that does not respond to moisturizing products, corticosteroids should be administered (Table 13.2).6 In the facial region, especially for periocular skin, less potent corticosteroids (e.g., fluticasone propionate 0.05%, mometasone furoate 0.1%, triamcinolone acetonide 0.1%) are recommended for shorter periods to prevent side effects such as cutaneous atrophy and the development of telangiectasia. In cases of Gram-positive bacterial superinfection (usually Staphylococcus aureus), topical antibacterial creams (mupirocin, fusidic acid, or gentamicin) should be applied.
Table 13.2
Relative Potencies of Representative Examples of Topical Corticosteroids
| Corticosteroid Class | Drug and Strength (%) |
| I. Very high potency | |
| II. High potency | |
| III-IV. Medium potency | |
| V. Lower-medium potency | |
| VI. Low potency | |
| VII. Lowest potency |
Controversy: Topical corticosteroids are often used without significant side effects. It is well known that systemic corticosteroids can cause glaucoma and cataracts, but the implications of topical corticosteroids are not yet clear. There is some evidence that potent topical corticosteroids used for long periods in periorbital sites may impact vision. In practice, neither weak nor potent topical corticosteroids tend to produce ocular complications when used to manage eyelid conditions.7
Topical calcineurin inhibitors such as tacrolimus (0.1% and 0.03%) and pimecrolimus (1%) are alternatives for those patients who require long-term topical management. Continuous application of these drugs increases the interval between exacerbations. Pimecrolimus 1% is approved for second-line use in children under 2 years of age and in adults with mild to moderate AD. The use of long-term topical calcineurin inhibitors does not carry the risks associated with topical steroids, such as skin atrophy. Thus, it is suitable for intertriginous and periocular skin.
Controversy: In 2006, the US Food and Drug Administration (FDA) highlighted the lack of long-term safety data and the theoretical risk of skin malignancy and lymphoma with prolonged use of calcineurin inhibitors. More recently, pimecrolimus has been reported to be effective in infants with AD, with sustained improvement over long-term intermittent use and no evidence of systemic immunosuppression. Therefore, some authors view the FDA warnings regarding the use of pimecrolimus in infants as no longer justified.8
Systemic Treatment.
Multiple forms of light therapy are beneficial for disease and symptom control. The most common source used is narrow-band ultraviolet B (UVB) rays. It can be indicated alone or in combination with corticosteroids, but calcineurin inhibitors should be avoided.
Oral steroids may be considered for short periods while other regimens are being initiated. Cyclosporin A, azathioprine, methotrexate, and mycophenolate mofetil (Cellcept) can be used off-label for the effective treatment of refractory atopic dermatitis.9 Omalizumab, a monoclonal anti-immunoglobulin E antibody used for the treatment of severe allergic asthma, is also under investigation.10
Complications
A disseminated herpes simplex eruption may occur (eczema herpeticum). Half of the patients with a generalized eruption have fever and systemic symptoms, and 10% experience associated eye involvement, mainly keratoconjunctivitis11 (Fig. 13.3). The impaired skin barrier is believed to create a more permissive environment for viral invasion. It has been shown that peripheral blood mononuclear cells from patients with a history of eczema herpeticum have a distinct immune response after herpes simplex virus 1 (HSV-1) exposure compared with those from patients without this complication.12
Seborrheic Dermatitis
Seborrheic dermatitis is a common inflammatory skin condition that occurs predominantly in areas with active sebaceous glands and is often associated with sebum overproduction. The skin changes are thought to result from an inflammatory response to Malassezia yeast, an organism commonly present in the skin.
Clinical Features
Characteristic symptoms of seborrheic dermatitis include scaling, erythema, and itching. The scalp, face, and chest are most commonly affected. In the face, the most frequent areas involved are forehead, medial eyebrows, upper eyelids, nasolabial folds, lateral aspects of the nose and the retroauricular area. Clinical diagnosis is easily achieved on the basis of characteristic location and appearance. Seborrheic dermatitis is a chronic and relapsing condition. Severe seborrheic dermatitis should suggest a possible association with human immunodeficiency virus (HIV) infection. Some neurologic disorders such as Parkinson disease also have a higher prevalence of seborrheic dermatitis. Rosacea and seborrheic dermatitis often coexist in the same patient.
Management
Antifungal azole agents such as topical ketoconazole are the mainstay of therapy. Other options used are topical corticosteroids and calcineurin inhibitors. Because of possible adverse effects such as skin atrophy, corticosteroids should be administered only for short periods. Regular application of emollients is also useful and recommended. Topical corticosteroids and calcineurin inhibitors are more effective in achieving total clearance of symptoms compared with placebo. However, there are no considerable differences between these drugs and azoles for short-term treatment.13 Topical ketoconazole can be applied daily without any concern related to side effects. In those patients who do not respond to it, a 1-week course of topical corticosteroid cream can be followed by calcineurin inhibitors, which can be maintained for 3 months.
Oral minocycline effectively decreases eyelid bacterial flora in patients with rosacea or blepharitis due to seborrheic dermatitis (Fig. 13.4). Therefore, systemic antibiotics can be considered for patients who do not response to topical treatments.14
Contact Dermatitis
Contact allergic dermatitis accounts for 2% to 4% of patients who seek dermatologic consultation, although the actual incidence is probably higher.
Clinical Features
The specific clinical manifestations depend on the causative agent of the dermatitis, the area where the compound is applied, the duration of contact, and the individual characteristics of the patient. Contact dermatitis caused by the use of cosmetics appears more frequently on the face, especially on the eyelids (Fig. 13.5). Clinically, it manifests with varying degrees of erythema, scaling, and itching. In the acute phase, vesicles and oozing are present. The chronic stages show scaling, xerosis, and lichenification (a process by which skin becomes hardened and leathery as a result of chronic scratching and/or rubbing) (Fig. 13.6). It can also manifest as eyelid swelling. Additionally, a bacterial superinfection can be seen.
Diagnosis
Contact dermatitis can be clinically suspected on the basis of a detailed patient history and can be easily confirmed by patch testing, if necessary. In addition to the standard battery and other available tests, depending on the medical history of the patient, all personal cosmetic products should be tested. Perfumes are the most common cause of contact allergic dermatitis, followed by cosmetics, preservatives, and hair dyes. Greater than 80% of contact allergic dermatitis appears in areas remote from the points of contact. For example, an allergic reaction to nail polish can manifest on the eyelids.
Controversy: The label “fragrance free” may not necessarily mean the product does not contain fragrance chemicals, but simply implies that no perceptible aroma is present. These products may possibly contain a masking fragrance that is used to cover up the odor of other ingredients.
Differential Diagnosis
The differential diagnosis of contact dermatitis includes all types of eczematous disorders. Irritant contact dermatitis can occur in anyone but is more frequent in people with a history of AD (Fig. 13.7). Irritant contact dermatitis presents as patches of itchy, scaly skin, or red rashes but can progress into oozing blisters. With strong irritants, a reaction may occur within minutes or hours of exposure. With weaker irritants, in contrast, it may take days or weeks for symptoms to appear.
Cutaneous mycosis can also mimic contact allergic dermatitis, manifesting as erythematous plaques with scaling and crusting but with more prominent edges and a whiter center (Fig. 13.8). A potassium hydroxide scraping sample should be taken from the skin lesions, and a culture should be made, especially if the clinical diagnosis is unclear.
Topical drugs can also produce irritant and allergic contact dermatitis, as well as contact urticaria, anaphylaxis, and photosensitivity. A thorough clinical history should identify any potential causative medicines (Table 13.3).15
Management
The mainstay of treatment is identification and avoidance of the offending agent. Topical corticosteroids can hasten the resolution of clinical symptoms and cutaneous signs. A medium-potency corticosteroid is usually indicated (Table 13.2) for a period of 1 to 2 weeks. Oral corticosteroid is indicated for those patients with more extensive eczema (e.g., prednisone 0.5 mg/kg for 1 week; for this short period, tapering is not necessary).
Other Inflammatory Disorders
Acne Rosacea
Acne rosacea, also called rosacea, is an inflammatory condition presenting with erythematous flushing, edema, telangiectasia, papules, pustules, and nodules on the face. Different clinical subtypes have been described: erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, ocular rosacea, and, more recently, granulomatous rosacea (Fig. 13.9). It is not clear whether there is a relationship between the different stages of rosacea that appear as the affliction worsens or if they are independent phases of the disease with a common phenotype.
Epidemiology
Rosacea typically presents in the third decade of life, with a peak incidence between 40 and 59 years of age. The prevalence of the disease ranges between 0.09% and 22%. The overall incidence rate for diagnosed rosacea in the United Kingdom has been reported to be 1.65 per 1000 person-years.16
Pathogenesis
The pathophysiology of rosacea is quite complex. Recent studies suggest that rosacea initially appears when the innate immune system responds to environmental stimuli, giving rise to vascular alterations and inflammation.17 Dilated blood and lymphatic vessels are seen on histologic specimens. Dysregulation of mediators and receptors implicated in neurovascular and neuroimmune communication may be crucial at early stages of this disease.18 Cathelicidin peptides may be involved as well. Mast cells, which are key mediators of cathelicidin-initiated skin inflammation, are increased throughout the dermis.19
Demodex folliculorum infestation is also involved in the pathogenesis of cutaneous and ocular rosacea. Demodex is a genus of tiny parasitic mites, which usually live in the hair follicles of humans. It is diagnosed by skin biopsy in cutaneous rosacea and by analyzing eyelashes under the light microscope in ocular rosacea (see Chapter 10). New techniques such as in vivo confocal microscopy could improve the diagnosis.20
A variety of potential triggering factors of rosacea have been described: UV light, extreme temperatures, spicy foods, alcohol, caffeine, and tomatoes. Some authors believe that these factors activate the peripheral sensory nerve endings that have been implicated in the pathophysiology of rosacea. Others believe there is an important genetic component to rosacea.
Controversy: The role of Demodex in rosacea and blepharitis is controversial. This ectoparasite can be found within the folliculosebaceous unit. A single dose of oral ivermectin or its topical application in some cases can be beneficial.21
Clinical Features
Early stages of the disease show different degrees of erythema associated with telangiectasia. The most common clinical presentation of rosacea is the papulopustular variety. It follows a progressive course, with intermittent periods of flare-up and remission.
Ocular Involvement
Ocular rosacea is present in 20% to 50% of patients with cutaneous rosacea16,22 (Fig. 13.10). Ocular symptoms are often improperly diagnosed, particularly when they occur without cutaneous lesions.22 The possibility of ocular rosacea should be considered in older patients with persistent red eyes and relapsing conjunctivitis–blepharitis.23
Posterior eyelid margin blepharitis or meibomitis can be present in all forms of rosacea, resulting in thickening of the secretions of the Meibomian glands with decreased normal flow of oil into the tear film. Permanent occlusion of the Meibomian glands can be seen after several years as a result of chronic eyelid inflammation. The absence of an oil component of the tear film can cause dry eye, which can be painful.
Some symptoms of early meibomitis present in patients with ocular rosacea are ocular dryness with burning sensation, morning crusting, light sensitivity, periodic blurry vision, and paradoxic reflex tearing. Erythema and thickening of the eyelid margin, conjunctival hyperemia and chemosis, and eyelid margin telangiectatic vessels are all visible to the naked eye.
Management
Management of rosacea, with or without ocular involvement, requires long-term planning, detailed patient counseling and prolonged, complex protocols. Hygiene measures is the mainstay of management, along with topical and systemic therapies.
▪ Metronidazole: Topical metronidazole 0.75% gel twice daily for cutaneous inflammatory rosacea is one of the most common treatments. Systemic metronidazole is another option, its effectiveness and tolerance having been demonstrated in a pediatric population.24 To obtain complete and lasting remission, a dose between 20 and 30 mg/kg per day for 3 months is recommended. Prolonged treatment is recommended in those patients with ocular keratitis and an associated corneal ulcer. Ocular rosacea in pediatric patients is often misdiagnosed, especially if cutaneous lesions are not present.24
▪ Azelaic acid: Azelaic acid 15% gel is another effective treatment. It appears to produce quicker results compared with metronidazole, possibly by downregulation of the cathelicidin pathway. Some patients develop stinging, burning, or itching. A new foam formulation of azelaic acid 15% is currently under investigation.25
▪ Tetracyclines: The standard systemic treatment recommended for inflammatory rosacea is tetracyclines such as minocycline or doxycycline. The only oral agent for rosacea approved by the FDA is a modified-release doxycycline 40-mg capsule.26 It is a new subantimicrobial, sustained-release, low-dose doxycycline for the treatment of papulopustular rosacea.27 Ocular rosacea that does not respond as expected to topical therapy and possibly leads to severe corneal involvement can be treated in an effective and safe way with oral doxycycline 40 mg administered daily for several months.23,28
▪ Ivermectin: Topical application of ivermectin 1% cream once a day has recently been shown to be significantly superior to metronidazole 0.75% cream, with a higher patient satisfaction and a similar incidence of adverse effects.29 Ivermectin shows antiparasitic activity, as well as anti-inflammatory effects, decreasing the cellular and humoral immune responses and eradicating Demodex folliculorum. Ivermectin is approved for cutaneous rosacea, but not enough experience in the lid margins has been reported in the literature. Rarely, ivermectin can cause discharge or excessive tearing, dry or itching eyes, pain or swelling of the eye, eyelid, or inner lining of the eyelid.
▪ Other treatments: Non–FDA-approved oral agents include tetracyclines, macrolides, metronidazole, and isotretinoin. β-adrenergic blockers such as propranolol have been used to suppress flushing reactions in rosacea. The combination therapy of doxycycline and propranolol has been used in a recent study demonstrating its clinical effect, decreasing flushing and the inflammatory lesions.30 Oral azithromycin has been effective in treating cutaneous papulopustular rosacea.31 Considerable improvement has been observed in ocular symptoms, eyelid alterations, and conjunctival hyperemia scores without significant adverse-effects. In patients with gastrointestinal reaction to doxycycline, azithromycin has proven equally effective and better tolerated. Mild burning after instillation is the only side effect reported.32
Urticaria and Angioedema
Urticaria
Chronic urticaria is defined by the presence of itchy wheals lasting 6 weeks or longer. Although most cases are considered to be idiopathic, in a subset of patients with chronic idiopathic urticaria, the condition is autoimmune in origin. High mean platelet volume, positive rheumatoid factor, and antinuclear antibodies were all significantly more prevalent in this group of patients.33
Urticarial, IgE-mediated reactions typically produce hives and an apparent thickening of the skin through swelling of the papillary dermis lasting less than 24 hours. Repeated, chronic, low-grade allergen exposure may lead to prolonged skin thickening, especially in thin skin areas such as the eyelid.
Triggers commonly include foods and insect bites. Paraneoplastic syndromes and autoimmune diseases can also cause urticaria. Physical urticaria can be caused by pressure and heat (e.g., in the periocular area after using swimming goggles or applying warm compresses for ocular meibomitis).
Angioedema
Angioedema, an urticaria-like allergic condition involving the deep dermis, subcuticular tissue, and, in some cases, the mucosa of the respiratory and digestive tracts is even more likely to present acutely. It is usually idiopathic, but a drug reaction and C1 inhibitor deficiency should always be excluded. Angioedema caused by genetic deficiency of C1 esterase inhibitor (C1-INH) manifests with recurrent bouts of inflammation that may be visibly isolated to the eyelids. Attacks, which involve circumscribed, nonpitting, subepithelial swelling lasting several days, may start during early childhood and may worsen at puberty. The type I variant is a true deficiency of C1-INH protein, and type II may have normal or increased levels of C1-INH but with a dysfunctional protein. Determination of C1-INH level, C4 level, and C1-INH activity should be performed to confirm the diagnosis.
Management.
Antihistamines are the mainstay of management for most cases of urticaria. There are classic (sedating) antihistamines (chlorpheniramine, hydroxyzine, diphenhydramine), second-generation antihistamines (cetirizine, loratadine, mizolastine), and third-generation antihistamines (desloratadine, fexofenadine). Bilastine is a new second-generation antihistamine recently approved for the symptomatic treatment of chronic urticaria.34 Rupatadine, another new antihistamine, has platelet-activating factor receptor antagonist activity and has shown anti-TNF-α activity in vitro. These additional anti-inflammatory effects may improve treatment efficacy.35 Some patients may benefit from concomitant histamine 2 (H2) antagonists.
Second-line therapies may be considered for those patients who do not respond to antihistamines. Oral corticosteroids, doxepin, montelukast, colchicine, danazol, and other systemic medications have been used. Optimal treatment protocols have yet to be determined. New medications for urticaria and angioedema such as omalizumab show promise.36
The treatment of C1 inhibitor deficiency differs from that of other types of angioedema. C1 inhibitor concentrate or fresh frozen plasma should be given in an emergency. Stanozolol or danazol are the treatment of choice for most patients. Other beneficial treatments for angioedema are tranexamic acid or ε-aminocaproic acid.
Differential Diagnosis of Angioedema or Eyelid Edema.
There is a broad spectrum of clinical entities and external factors that can cause eyelid edema.37
▪ Drugs: Many medications such as acetaminophen, aspirin, nonsteroidal anti-inflammatory drugs, among others can induce eyelid edema through generalized fluid retention, angioedema, urticaria, or topical blepharoconjunctivitis.
▪ Allergies: Allergic conditions in the periocular area include seasonal and perennial allergies, as well as vernal keratoconjunctivitis, contact dermatitis, and drug-induced allergic blepharoconjunctivitis. All are hypersensitivity reactions that can result in swollen eyelids, chemosis, ocular surface hyperemia, tearing, and a scaly eczematous rash.
▪ Dermal fillers: Dermal fillers used around the eyes for cosmetic or reconstructive purposes can induce allergic reactions. Hyaluronic acid is probably the safest dermal filler. Other permanent dermal fillers such as polyacrylamide and polyalkylimide can produce local and regional delayed adverse effects. Tender inflammatory nodules, as well as an urticaria-like reaction with generalized edema affecting the eyelids, can be seen (Fig. 13.11). Dermal fillers injected around the eye to correct the tear trough can cause local edema and lumps when injected superficially. Off-label use of fillers in the glabella should be undertaken with caution, as they have caused irreversible blindness.38
▪ Thyroid eye disease: Commonly causes bilateral eyelid, conjunctival, and orbital edema in older patients. Lagophthalmos, eyelid retraction, and proptosis can also be present. The quiescent phase can mimic eyelid edema. Trauma such as surgery during the active phase of thyroid eye disease may exacerbate the clinical course.
▪ Melkersson-Rosenthal syndrome: Characterized by noncaseating granulomas centered around the lymphatic channels with the clinical triad of facial palsy, facial edema, and lingua plicata. The facial edema is classically perioral, but eyelid edema may also be present or be the only sign of facial swelling. Eyelid edema, initially intermittent but perhaps progressing to become constant, is painless and nonpitting. Bilateral or unilateral cases have been reported.
▪ Blepharochalasis: Bilateral or unilateral recurrent episodes of painless, nonpitting upper or lower eyelid edema starting typically in young adult women and decreasing in frequency over time. Active episodes last an average of 2 days, making them frustratingly difficult to diagnose and arrest. Stigmata of recurrent episodes include hyperpigmented, thin, wrinkled eyelids, sometimes described as ‘crepe paper’ eyelids.
▪ Whole body edema: May present first or most notably with eyelid edema, which is typically worse early in the morning after a prolonged dependent posture, with gradual improvement occurring throughout the day. Differential diagnosis includes cardiac disease, renal disease, hepatic disease, low-protein states, lymphatic obstruction, and hypothyroidism.
▪ Lymphedema: Manifests as localized swelling as a result of accumulation of extracellular fluid, which usually drains through the lymphatic system. Lymphedema may affect the eyelid skin, the posterior lamella, or the palpebral conjunctiva, resulting in tissue fibrosis. It can be seen after facial trauma or surgery that interrupts lymphatic outflow.
▪ Keratoconjunctivitis sicca, or “dry eye”: As the surface of the eye dries, the conjunctiva may paradoxically swell and the chemosis can spill over into the palpebral conjunctiva, causing eyelid edema.
Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis form a spectrum of a rare and life-threatening disorder usually caused by drug exposure. SJS is characterized by severe erosions of at least two mucosal surfaces with extensive superficial necrosis of the lips and mouth and purulent conjunctivitis. Toxic epidermal necrolysis (TEN) presents with a large denuded area and extensive areas of epidermal necrosis. These entities are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions. They can be distinguished by the extent of skin detachment.
Pathogenesis
There are many precipitating factors implicated in SJS: drugs, bacterial infections such as Mycoplasma pneumoniae, and fungal and viral infections, among others. Medications are the most common inciting factors in SJS and almost the only cause in those patients with TEN. Many drugs have been implicated. Most frequent are nonsteroidal anti-inflammatory drugs, sulfonamides, and antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, lamotrigine, valproic acid, among others). Others are trimethoprim-sulfamethoxazole (Bactrim) and allopurinol.
Clinical Features
Patients with SJS usually have a distinct prodrome of an upper respiratory illness, with fever, cough, rhinitis, diarrhea, and malaise. A few days later, a symmetric, red macular eruption that progresses to central blister formation and areas of epidermal necrosis can be seen. Skin involvement may be limited to a few targetlike lesions or may be extensive. Lips show hemorrhagic crusts, with denudation of the mucosa. There is usually a generalized lymphadenopathy. Patients with TEN develop fever, stinging eyes, and pain upon swallowing, usually 1 to 3 days before the skin manifestations appear. Initial lesions have a characteristic dusky-red color and progress to necrolytic lesions with epidermal detachment, which appears first in the trunk and then spreads to the neck, face, and proximal upper extremities. Characteristically, the soles and palms can be involved in the early stage. More than 90% of the patients have erythema and erosions of the oral, ocular, and genital mucosae. The epithelium of the respiratory tract can be affected in 25% of the patients.
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