Clinics in Dermatology (2015) 33, 217–226
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis☆ Alok Vij, MD ⁎, Wilma F. Bergfeld, MD Department of Dermatology and Dermatopathology, Cleveland Clinic Foundation, 9500 Euclid Ave, Desk A61, Cleveland, OH 44195, USA
Abstract Eyebrows, eyelashes, and eyelids are cosmetically and functionally important periocular landmarks that offer insights into a patient’s emotional state. Several pathologies exist with respect to the eyebrows, eyelashes, and eyelids. Madarosis refers to loss of the eyebrows or eyelashes; milphosis refers specifically to eyelash loss. Excess growth of eyelash hair is termed trichomegaly. Excess skin in the upper or lower eyelids is called dermatochalasis. Pathology of these important structures can be reflective of important local and systemic disease processes. © 2015 Published by Elsevier Inc.
Anatomy The eyebrows are arched eminences of hair-bearing skin above the eyes which give shape and character to an individual’s face, in addition to protecting the eyes from sweat.1 Eyelashes protect the globe from irritants and foreign bodies through their stimulation of the closing reflex.2 Fibers of several muscles of facial expression insert into the skin underlying the eyebrow, allowing for changes in contour to reflect inner emotions (Figure 1).3 Each eyebrow hair is short and stiff, growing at an angle from the line of the brow.4 The diameter of the hairs can be thicker, as in Caucasians, or thinner, as in Asians, than scalp
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All images have been de-identified, except in case of a signed consent form allowing publication of images on file in the Department of Dermatology of the Cleveland Clinic Foundation. ⁎ Corresponding author. Tel.: + 1 2164442651; fax: + 1 2166365151. E-mail address: [email protected] (A. Vij). http://dx.doi.org/10.1016/j.clindermatol.2014.10.013 0738-081X/© 2015 Published by Elsevier Inc.
hair.5,6 The brow can be divided into thirds: medially, lying below the orbital margin with vertical hair growth; the midportion, along the orbital margin with oblique to horizontal growth; and lateral, above the orbital margin, with horizontal growth. Hair density thins from medial to lateral, so organic hair loss is often more apparent laterally.7 Eyelash hairs originate anterior to the palpebral muscle and are set obliquely. The denser upper eyelashes curve upward, while the lower lashes close downward; this prevents interlacing while the eye is closed.4 Eyelash hairs are oval in all races and universally lack arrector pili muscles. Eyelash hairs of Asians are fewer but thicker and with less curvature than those of Caucasians.8 The eyelids are bilamellar structures, with anterior and posterior lamellae.9 The anterior lamella consists of skin and the loosely adherent orbicularis oculi muscle, which can be divided into pretarsal, preseptal, and orbital segments. The pretarsal orbicularis is fixed to the tarsal plate of both upper and lower eyelids. The posterior lamella is composed of the tarsal plate and the conjunctiva. The tarsal plate provides
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Fig. 1
Surface anatomy of the eyebrows and eyelashes.
structural support to the eyelid. The conjunctiva is a stratified squamous nonkeratinizing epthielial layer, which is the most posterior layer of the eyelid (Figure 2).10
Eyebrow and eyelash loss Milphosis and madarosis can be a presenting or associated sign of many diseases. Table 1 includes a broad differential diagnosis for madarosis, sorted by ophthalmologic, dermatologic, and systemic disease. Ophthalmologic causes of milphosis include infectious and inflammatory forms of blepharitis. One effective classification of blepharitis differentiates between anterior and posterior forms based on the location of the inflamma-
Fig. 2 Cross sectional anatomy of the eyelid. The skin and orbicularis make up the anterior lamella; the tarsal plate and conjunctiva make up the posterior lamella.
tion related to the gray line, which separates the skin and muscle (anterior) from the tarsal plate and conjunctiva (posterior). Anterior blepharitis, which may present with presents with itching, burning, tearing, foreign body sensation, and photophobia, can be caused by staphylococcal, seborrheic, and Demodex-related etiologies; posterior blepharitis, presenting with a “foamy” tear film or plugging of the Meibomian orifices, may be caused by any form of Meibomian gland dysfunction.11 Staphylococcal infection usually presents with collarettes, which are hard scales found surrounding and fixed to individual lashes.12 Seborrhea presents with a greasy scale crust also called scruff. Infestation with Demodex folliculorum presents with sleeves, cyclindrical scales connected to the lash root.13,14 Hair loss from any of these causes results from persistent follicular inflammation, rubbing, or secondary infection. It may be scarring or nonscarring. Rosacea-related posterior blepharitis presents with telangiectasia at the eyelid margin and may include other signs or symptoms of rosacea, such as facial flushing, acneiform papules, or phymatous change of the forehead, nose, and chin. If inflammation extends to the anterior lid margin, milphosis may occur (Figure 3).15 Many dermatologic causes of eyebrow and eyelid loss exist, many of which are discussed elsewhere in this series. Atopic dermatitis classically includes “Hertoghe’s sign,” loss of the lateral third of the eyebrows from constant rubbing and scratching,16 in addition to a Dennie Morgan fold, an infraorbital fold due to lower lid edema.17 Seborrheic dermatitis is another pruritic dermatosis that may induce madarosis due to persistent perifollicular inflammation as well as manipulation (Figure 4).18 Hair loss from follicular mucin deposition can result from a malignant inflammatory process, such as cutaneous T-cell lymphoma,19 or as a component of other neoplastic or inflammatory conditions.20 Classically, the lymphomatous follicular mucinosis consists of indurated, waxy plaques of the eyebrows and forehead, although any hair-bearing site may be involved (Figure 5). Persistent contact dermatitis may also induce hair loss; allergic etiologies predominate over irritant in relation to eyelid dermatitis. Frequent allergens include fragrance, metals, and topical antibiotics.21 Psoriatic plaques involving the eyebrow and eyelid are found in approximately 4-10% of patients.22
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis Table 1
Differential diagnosis for madarosis
System
Category
Differential Diagnosis
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Table 1 (continued) System
Ophthalmologic Infectious
Dermatologic
Systemic diseases
Staphylococcal blepharitis Demodex folliculorum blepharitis Trachoma Inflammatory Seborrheic blepharitis Rosacea blepharitis Posterior blepharitis Papulosquamous Atopic dermatitis disorders Contact dermatitis Seborrheic dermatitis Psoriasis Lichen planus Sclerotic Linear scleroderma disorders (en coup de sabre) Parry-Romberg syndrome Sclerodermoid graftversus-host disease Disorders of Lamellar ichthyosis keratinization Monilethrix Hair shaft disorders Pili torti Inflammatory Frontal fibrosing alopecia hair disorders Graham-Little-PiccardiLasseur syndrome Alopecia areata Ulerythema ophyrogenes NonTelogen effluvium inflammatory hair disorders Anagen effluvium Trichotillomania Bullous disease Epidermolysis bullosa Pemphigus foliaceus Other Rosacea Follicular mucinosis Sarcoidosis Erythema multiforme Familial acanthosis nigricans Infectious Leprosy
Category
Tuberculosis (lupus vulgaris) Secondary or tertiary syphilis Erysipelas Folliculitis or furunculosis Trichodysplasia spinulosa Herpes simplex or zoster HIV Molluscum contagiosum Dermatophytes: Trichophyton, Microsporum
Endocrine
Autoimmune disease
Neoplasia Neoplasia
Drugs
Toxic
Nutritional
Trauma
Adapted.92
Differential Diagnosis Deep Fungal: Coccidiomycosis, Paracoccidiomycosis Phthriasis Hypothyroidism Hyperthyroidism Hypoparathyroidism Hyperparathyroidism Hypopituitarism Sheehan's syndrome Amyloidosis Discoid lupus Vogt Koyanagi Harada syndrome Sebaceous carcinoma Squamous cell carcinoma Basal cell carcinoma, Sclerosing sweat duct carcinoma, Leukemia cutis Cutaneous lymphoma Seborrheic keratosis Leiomyoma Mastocytoma Anti-thyroid drugs Anticoagulants Lipid lowering agents Propranolol Valproate Barbiturates Bromocroptine Immunosuppressants Systemic retinoids Chemotherapies MMR vaccination Epinephrine Botulinum toxin Quinine Gold Hypervitaminosis A Thallium Arsenic Bismuth Mercury Biotin deficiency Iron deficiency Zinc deficiency Hypoproteinemia Marasmus Radiation injury Tattoo Physical, chemical, or thermal injuries
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Fig. 3 A 39-year-old patient with granulomatous rosacea of the eyelids, resulting in partial milphosis of both upper and lower eyelids bilaterally. She had associated telangiectasia of the lid margin, facial flushing, and a foreign body sensation of the eyes.
Many inflammatory and noninflammatory causes of hair loss can affect the eyebrows and eyelashes as well as the scalp. Frontal fibrosing alopecia, a clinical variant of lichen planopilaris classically affecting postmenopausal women, is a form of scarring alopecia that results in loss of frontal hairline and eyebrows (Figure 6).23 Additionally, GrahamLittle-Piccardi-Lasseur syndrome consists of lichen planopilaris of the scalp with nonscarring loss of the eyebrows, eyelashes, axillary, and pubic hair.24 Lichen planopilaris is marked by perifollicular keratotic scale and erythema.25 Alopecia areata is an incompletely understood entity thought to be mediated by autoimmune damage after loss of the immune privilege of the follicular unit.26 Alopecia areata is marked by “exclamation point hairs,” tapering as they approach a smooth, bald patch of the scalp, which may have a peach to yellowish hue. Alopecia areata may affect the eyebrows or eyelashes as an isolated finding, with patchy scalp involvement, or as a part of alopecia universalis
Fig. 4 A patient with seborrheic dermatitis and erythemotelangiectatic rosacea. Due to persistent inflammation, his lateral eyebrows were lost. His eyebrows did recover after sufficient treatment of his dermatitis.
A. Vij, W.F. Bergfeld
Fig. 5 Alopecia mucinosa, or follicular mucinosis due to cutaneous T cell lymphoma, of the temporal scalp and eyebrow more than eyelashes. This patient had prominent CD-30 positivity within the lymphomatous infiltrate, and was responded well to brentuximab vedotin; however, she never regrew hair within the alopecic plaques.
(Figure 7). When localized to the eyebrows, there is rarely involvement of other areas of the body.27 The most common form of hair loss is telogen effluvium, marked by shedding of an extraordinarily high percentage of otherwise normal telogen hairs. Usually brought on by acute systemic disease, surgery, emotional stress, or other severe changes in normal physiology, it may result in diffuse thinning of eyebrows and eyelashes in addition to scalp hair.28 Anagen effluvium may be induced by cytotoxic chemotherapies, resulting in decreased hair density globally.29 Trichotillomania and other neurodermatoses may result in picking, plucking, or otherwise manipulating the eyebrows and eyelashes in response to external stressors (Figure 8); these actions may occur in concert with co-morbid psychiatric illness or as an isolated stress-response phenomenon.30
Fig. 6 Frontal fibrosing alopecia. Note the band-like alopecic plaque of the frontal hair line, which has been replaced by an atrophic, shiny white plaque with lonely hair fibers. The patient presented with intact eyebrows, but her inflammatory alopecia eventually caused bilateral madarosis (seen here with makeup).
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Fig. 7 Madarosis of the eyebrows and eyelashes in a patient with alopecia universalis.
In addition to local ophthalmologic and dermatologic causes of hair loss, systemic diseases can have a major effect on hair density of the eyebrows and eyelashes. Infections of all etiologies can impact the eyelashes and eyebrows. Classic “leonine facies” of advanced leprosy include bilateral eyebrow loss,31 but lupus vulgaris is another mycobacterial infection that may induce hair loss32; secondary and tertiary syphilis may result in patchy hair loss of the eyelashes or eyebrows as well as the scalp.33 Many bacterial, viral, and fungal diseases may also thin or obliterate the hairy periocular structures (Figure 9). Many endocrinopathies may cause madarosis as well. Perhaps the most well-known association links hypothyroidism with loss of the lateral third of the eyebrows; this has been coined “Queen Anne’s sign,” after the Danish Queen’s thin eyebrows and suspected goiter.34 Hyperthyroidism, which may induce increased brittleness of the hair, may present with thin, broken off eyelashes.35 Discoid lupus may present with scarring alopecia and dyspigmentation of any hair bearing site (Figure 10). Scleroderma, particularly the linear variant in children, known as “en coup de sabre,” can present with poliosis, localized whitening of the hairs, before circumscribed madarosis within an advancing, sclerotic plaque (Figure 11).36 Its craniofacial counterpart, Parry Romberg
Fig. 8 Madarosis of the mid-portion of the lateral brow and eyelashes in a patient with trichotillomania. Note the coarse terminal hairs growing back within the alopecic patches which were too short for the patient to pluck.
Fig. 9 A patient with zoster ophthalmicus with obliteration of the left eyebrow within the involved dermatome.
syndrome, consists of central nervous system disturbances, including seizures, with hemifacial atrophy and loss of pilosebaceous units.37 Sclerodermoid graft-versus-host disease may induce the same changes.38 Benign and malignant neoplastic conditions may obliterate hairs by direct extension (Figure 12). Medication induced hair loss may be first noticed in the brows and lashes. Among dermatologic drugs, steroid-sparing immunosuppressants like methotrexate,39 mycophenolate mofetil,40 and azathioprine41 may all induce hair loss; hair loss can be a doselimiting side effect of the systemic retinoids acitretin, etretinate, isotretinoin, and bexarotene.42 Hypervitmainosis A, along the same lines, is associated with hair loss,43 as are toxic levels of arsenic,44 gold,45
Fig. 10 A patient with systemic lupus erythematosus with discoid cutaneous lesions. Her left eyebrow has an alopecic patch due to her chronic cutaneous lupus. Note the hyperpigmentation, hypopigmentation, scarring, and atrophy within the involved plaques.
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A. Vij, W.F. Bergfeld Table 2
Differential diagnosis for eyelash trichomegaly
Type
Frequency
Congenital
Common
Acquired
Fig. 11 A patient with “en coup de sabre,” a form of linear scleroderma involving the frontal scalp and forehead. He had stable madarosis of the left eyebrow despite softening of the sclerotic plaque of his forehead with methotrexate.
mercury,46 and selenium.47 Functional deficiency of biotin, iron, and zinc as well as protein and total calorie malnutrition are associated with hair loss.48 Finally, locally destructive scarring processes can prevent hair regrowth.49
Medicationinduced
Fig. 12 Squamous cell carcinoma involving both eyelids and the periorbit. Note the loss of lateral lower eyelashes, resulting from invasive tumor disrupting the follicular units.
Cornelia de Lange syndrome Oliver-McFarlane syndrome Uncommon Congenital heart disease Familial trichomegaly Hermansky-Pudlak syndrome Rare Aghaei-Dastgheib syndrome Cone-rod dystrophy Goldstein-Hutt syndrome Phylloid hypomelanosis Common Atopic dermatitis HIV infection Uveitis Vernal conjuntivitis Rare Alopecia areata Dermatomyositis Malignancy Systemic lupus erythematosus Frequent Prostaglandin analogs Common
Cetuximab Erlotinib Uncommon Gefitinib Panitumumab Interferon alpha Rare Cyclosporine Tacrolimus Topiramate Zidovudine
Eyelash trichomegaly Eyelash trichomegaly is defined as eyelashes which are increased in length, thickness, and pigmentation. Trichomegaly may appear congenitally as a familial trait or in association with a genetic syndrome; it may be an acquired finding which may be a sign of immune dysfunction or accompany treatment with a local or systemic medication. Table 2 offers a differential diagnosis for trichomegaly.
Differential Diagnosis
Adapted.53
Many congenital syndromes may have trichomegaly as a rare feature, but only two, Oliver-McFarlane syndrome and Cornelia de Lange syndrome, count eyelash trichomegaly as a defining diagnostic criterion. Oliver-McFarlane syndrome is a rare autosomal recessive syndrome, with affected patients having retinal pigment degeneration, dwarfism, and mental retardation that may exist in association with hypothyroidism, hypogonadism, or growth hormone deficiency.50 Cornelia de Lange syndrome includes eyelash trichomegaly in association with small stature and malformations of the musculoskeletal, cardiac, neurologic, and gastrointestinal systems. The patients have characteristic facies, including high, arched eyebrows that meet in the midline (synophris) and extend down the nasal bridge; dysplastic, low set ears; short nose with depressed nasal bridge and long, prominent philtrum; thin upper lip; downturned oral commissures; and flattened midface.51 Other clinical syndromes frequently present with trichomegaly, but this finding is not required for diagnosis. Hermansky-Pudlak syndrome frequently has trichomegaly; this syndrome consists of oculocutaneous albinism and a
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis Table 3
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Congenital syndromes with hypertrichosis of the eyelashes and associated features
Syndrome
Associated Features
Aghaei-Dastgheib syndrome Cone-rod dystrophy Cornelia de Lange syndrome Goldstein-Hutt syndrome Hermansky-Pudlak syndrome Oliver-McFarlane syndrome Phylloid hypomelanosis
Generalized hypertrichosis, bilateral nipple retraction, accessory nipple Cone-rod amaurosis, hypertrichosis Synophrys, facial and musculoskeletal anomalies, small stature, developmental delay Cataracts, hereditary spherocytosis Oculocutaneous albinism, platelet storage pool deficiency, ceroid lipofuscin accumulation Pigmentary retinal degeneration, dwarfism, mental retardation Hypopigmented macules; chromosome 13 q anomalies; cerebral, ocular, and skeletal defects
Adapted.53
bleeding diathesis related to an absence of platelet dense bodies. Additionally, accumulation of ceroid lipofuscin in lysosomes is thought to lead to pulmonary fibrosis, often fatal, and granulomatous colitis.52 Congenital trichomegaly may present in infants with congenital heart disease; this association was initially attributed to high degrees of parental consanguinity, although recent reports have brought that association into question.53,54 Many other syndromes have been described in which rare reports of trichomegaly exist. These have been well classified elsewhere, and are presented in Table 3.55 As with congenital conditions, eyelash trichomegaly may occur commonly or rarely in concert with local cutaneous, ophthalmologic, or systemic disease processes. Eyelash trichomegaly has rarely been reported in alopecia areata,56 autoimmune connective tissue diseases like systemic lupus erythematosus57 and dermatomyositis,58 HIV infection,59 and malignancies.60 Frequently, patients with atopic diseases such as atopic dermatitis61 and allergic rhinitis62 may have acquired
trichomegaly. Uveitis of any cause is associated with a statistically significant increased eyelash length compared to age- and sex-matched controls. This finding is thought to be mediated by local alterations of cytokine and growth factor expression.63 Vernal keratoconjunctivitis, bilateral allergic conjunctivitis, is associated with longer upper eyelashes, the length of
Fig. 13 Panel A, Eyelashes of a patient before starting topical bitamoprost. Panel B, Eyelashes of a patient after using topical bitamoprost daily for 6 months.
Fig. 14 Panel A, Acute episode of eyelid edema in a patient with blepharochalasis. Panel B, Redundant and lax skin of the lower eyelid as a consequence of serial episodes of profound edema.
224 Table 4
A. Vij, W.F. Bergfeld Differential diagnosis for dermatochalasis
Normal changes of aging Lax eyelid syndrome Congenital Cutis Laxa Ehlers-Danlos syndrome Plasma cell dyscrasia Amyloidosis Systemic Lupus Erythematosus Sweet’s syndrome Penicillamine therapy Blepharochalasis
which positively correlate to symptoms. Trichomegaly may be a multifactorial compensatory mechanism, induced to increase local defenses to exacerbating factors of sun, wind, and foreign particles.64 Treatment with cyclosporine eye drops was associated with decreased eyelash length in patients with vernal keratoconjunctivitis.65 This finding contrasts with the known association of cyclosporine treatment inducing eyelash trichomegaly.66 Many medications have been associated with trichomegaly. Topical prostaglandins, for instance, so regularly and reliably produce trichomegaly that they are now offered as cosmetic treatments to enhance eyelash appearance (Figure 13). 67 Epidermal growth factor receptor inhibitors have become commonly used oncologic treatments due to their safety with good antitumor activity against a broad range of epithelial carcinomas. Cetuximab and panitumumab are monoclonal antibodies which inhibit the aberrant epidermal growth factor receptor expression extracellularly; erlotinib and gefitinib are small molecule tyrosine kinase inhibitors intracellularly interrupt the same signal transduction pathway. Cetuximab and erlotinib more commonly induce eyelash trichomegaly than panitumumab and gefitinib.68 Immunomodulatory medications as well may induce trichomegaly. Eyelash trichomegaly may occur in the minority of patients treated with systemic cyclosporine and tacrolimus69; rarer still is the induction of trichomegaly with various interferons.70–72 The antiretroviral medication zidovudine73 and the antiepileptic medication topiramate74 rarely cause eyelash trichomegaly as well.
Histopathological studies indicate that atrophy of the epidermis and dermis are responsible for the sagging eyelids, with preservation of the orbicularis oculi muscle.76 The most characteristic findings included loss of elastic fibers, widened spacing between collagen bundles, and dilation of lymph vessels with resultant lymphedema. 77 These histologic findings may occur simply as a consequence of the aging process, but they also correlate with the major pathologic changes found in syndromic variants of dermatochalasis. The most common syndromic cause of dermatochalasis is cutis laxa, which can itself be a hereditary disease or an acquired condition. Cutis laxa is characterized by wrinkled, inelastic, redundant skin due to defects in the elastic fibers or other molecules of the extracellular matrix; when the eyelids are involved, dermatochalasis is the result. The hereditary form of cutis laxa can be associated with a number of systemic findings,78 or it can be associated with a number of metabolic diseases.79 Acquired cutis laxa has been reported in concert with plasma cell dyscrasia with80 or without81 systemic lupus erythematosus, as a postinflammatory change in Sweet’s syndrome,82 and as a result of penicillamine therapy,83 among others.84 Amyloidosis is also thought to be a risk factor for dermatochalasis, although its association with acquired cutis laxa obscures a potential direct relationship.85,86 EhlersDanlos Syndrome, a heterogenous group of inherited defects of collagen, may predispose to dermatochalasis.87 Angioedema has been reported to cause dermatochalasis,88 most likely as an end-stage result from multiple bouts of extreme edema, resulting in altered lymphatic drainage. Persistent edema from nephrotic syndrome89 or thyroid orbitopathy90 may induce similar changes. Blepharochalasis is a rare, idiopathic disease characterized by recurrent episodes of acute eyelid edema (Figure 14), resulting eventually in lax, atrophic skin.91–93 Self-induced trauma has been reported to cause blepharochalasis.94
Conclusions In addition to giving insight to an individual’s emotional state, the periocular structures can provide a wealth of information to a host of local and systemic disease states. Careful observation is required to take note of changes of the eyebrows, eyelashes, and eyelids. A wide differential exists for changes in these structures.
Dermatochalasis Dermatochalasis most commonly affects the elderly, although it can present as early as 40 in acquired cases and 20 in congenital cases. Redundant skin may predispose to loss of the superior visual field or may cause upper eyelid entropion or lower eyelid ectropion or retraction. Acquired forms of dermatochalasis in younger individuals without systemic associations has been termed the lax eyelid syndrome, akin to a localized progeria of the eyelids.75 See Table 4 for a differential diagnosis for dermatochalasis.
References 1. Margulis A, Amar D, Billig A, et al. Periorbital reconstruction with the expanded pedicled forehead flap. Ann Plast Surg. 2013. [epub ahead of print]. 2. Hwang K. Surgical anatomy of the upper eyelid relating to upper blepharoplasty or blepharoptosis surgery. Anat Cell Biol. 2013;46:93-100. 3. Kikkawa DO, Lemke BN, Dortzbach RK. Relations of the superficial musculoaponeurotic system to the orbit and characterization of the orbitomalar ligament. Ophthal Plast Reconstr Surg. 1996;12:77-88.
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis 4. Epstein J. Facial hair restoration: Hair transplantation to eyebrows, beard, sideburns, and eyelashes. Facial Plast Surg Clin North Am. 2013;21:457-467. 5. Price KM, Gupta PK, Woodward JA, et al. Eyebrow and eyelid dimensions: An anthropometric analysis of African Americans and Caucasians. Plast Reconstr Surg. 2009;124:615-623. 6. Kunjur J, Sabesan T, Ilankovan V. Anthropometric analysis of eyebrows and eyelids: An inter-racial study. Br J Oral Maxillofac Surg. 2006;44:89-93. 7. Haddad D, Gemperli R. Surgical correction of aesthetically deformed eyebrows using local transposition flaps. Aesthetic Plast Surg. 2010;34: 734-737. 8. Na JI, Kwon OS, Kim BJ, et al. Ethnic characteristics of eyelashes: A comparative analysis in Asian and Caucasian females. Br J Dermatol. 2006;155:1170-1176. 9. Codner MA, Hanna MK. Applied anatomy of the eyelids and orbit. In: Nahai F, ed. The Art of Aesthetic Surgery: Principles and Techniques. St. Louis, MO: Quality Medical Publishing; 2005. p. 625-650. 10. Alghoul M, Pacella SJ, McClellan WT, et al. Eyelid reconstruction. Plast Reconstr Surg. 2013;132:288 e-302 e. 11. Lindsley K, Matsumura S, Hatef E, et al. Interventions for chronic blepharitis. Cochrane Database Syst Rev. 2012;5:CD005556. 12. O’Brien TP. The role of bacteria in blepharitis. Ocul Surf. 2009;7: S21-S22. 13. Jackson WB. Blepharitis: Current strategies for diagnosis and management. Can J Ophthalmol. 2008;43:170-179. 14. Hom MM, Mastrota KM, Schachter SE. Demodex. Optom Vis Sci. 2013;90(7):e198-e205. 15. Vieira AC, Hofling-Lima AL, Mannis MJ. Ocular rosacea—a review. Arq Bras Oftalmol. 2012;75:363-369. 16. Nagaraja Kanwar AJ, Dhar S, et al. Frequency and significance of minor clinical features in various age-related subgroups of atopic dermatitis in children. Pediatr Dermatol. 1996;13:10-13. 17. Schram MR, Leeflang MM, et al. Validation and refinement of the Millenium Criteria for atopic dermatitis. J Dermatol. 2011;36:850-858. 18. Ishida M, Iwai M, Yoshida K, et al. Adult T-cell leukemia/lymphoma accompanying follicular mucinosis: A case report with review of the literature. Int J Clin Exp Pathol. 2013;6:3014-3018. 19. Mir-Bonafé JM, Cañueto J, Fernández-López E, et al. Follicular mucinosis associated with nonlymphoid skin conditions. Am J Dermatopathol. 2013. [Epub ahead of print]. 20. Dessinioti C, Katsambas A. Seborrheic dermatitis: Etiology, risk factors, and treatments: Facts and controversies. Clin Dermatol. 2013;31:343-351. 21. Amin KA, Belsito DV. The aetiology of eyelid dermatitis: A 10-year retrospective analysis. Contact Dermatitis. 2006;55:280-285. 22. Zhu F, Tao JP. Bilateral upper and lower eyelid severe psoriasiform blepharitis: Case report and review of the literature. Ophthal Plast Reconstr Surg. 2011;27:e138-e139. 23. Lencastre A, Tosti A. Images in clinical medicine. A receding hairline. N Engl J Med. 2013:e2. 24. Laszlo FG. Graham-Little-Piccardi-Lasseur syndrome: Case report and review of the syndrome in men. Int J Dermatol. 2013. [epub ahead of print]. 25. Cevasco NC, Bergfeld WF, Remzi BK, et al. A case-series of 29 patients with lichen planopilaris: The Cleveland Clinic Foundation experience on evaluation, diagnosis, and treatment. J Am Acad Dermatol. 2007;57:47-53. 26. Ito T. Recent advances in the pathogenesis of autoimmune hair loss disease alopecia areata. Clin Dev Immunol. 2013;2013:348546. 27. Finner AM. Alopecia areata: Clinical presentation, diagnosis, and unusual cases. Dermatol Ther. 2011;24:348-354. 28. Bergfeld WF, Mulinari-Brenner F. Shedding: How to manage a common cause of hair loss. Cleve Clin J Med. 2011;68:256-261. 29. Kanwar AJ, Narang T. Anagen effluvium. Indian J Dermatol Venereol Leprol. 2013;79:604-612.
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30. Bergfeld W, Mulinar-Brenner F, McCarron K, et al. The combined utilization of clinical and histologic findings in the diagnosis of trichotillomania. J Cutan Pathol. 2002;29:207-214. 31. Krishnan A, Kar S. Bilateral madarosis as the solitary presenting feature of multibacillary leprosy. Int J Trichology. 2012;4:179-180. 32. Miteva L. Alopecia: A rare manifestation of lupus vulgaris. Int J Dermatol. 2011;40:659-661. 33. Hernanez-Bel P, Unamuno B, Sanchez-Carazo JL, et al. Syphilitic alopecia: A report of 5 cases and a review of the literature. Actas Dermosifiliogr. 2013;104:512-517. 34. Lane Furdell R. Eponymous, anonymous: Queen Anne’s sign and the misnaming of a symptom. J Med Biogr. 2007;15:97-101. 35. Jordan DR, Ahuja N, Khouri L. Eyelash loss associated with hyperthyroidism. Ophthal Plast Reconstr Surg. 2002;18:219-222. 36. Pierre-Louis M, Sperling LC, Wilke MS, et al. Distinctive histopathologic findings in linear morphea (en coup de sabre) alopecia. J Cutan Pathol. 2013;40:580-584. 37. Borodic GE, Caruso P, Acquardo M, et al. Parry Romberg syndrome vasculopathy and its treatment with Botulinum toxin. Ophthal Plast Reconstr Surg. 2014;30:e22-e25. 38. Nassar A, Tabbara KF, Aljurf M. Ocular manifestations of graft-versushost disease. Saudi J Ophthalmol. 2013;27:215-222. 39. Chan ES, Cronsterin BN. Mechanisms of action of methotrexate. Bull Hosp Jt Dis. 2013;71:5-8. 40. Tse KC, Tang CS, Lio WI, et al. Quality of life comparison between corticosteroid- and-mycofenolate mofetil and corticosteroid- and-oral cyclophosphamide in the treatment of severe lupus nephritis. Lupus. 2006;15:371-379. 41. Sood A, Midha V, Sood N, et al. Long term results of use of azathioprine in patients with ulcerative colitis in India. World J Gastroenterol. 2006;12:7332-7336. 42. Chappell JA, Chu MB, Martin K, et al. Acitretin-induced poliosis with concurrent alopecia. J Drugs Dermatol. 2012;11:247-249. 43. Cheruvattath R, Orrego M, Gautam M, et al. Vitamin A toxicity: When one a day doesn't keep the doctor away. Liver Transpl. 2006;12: 1888-1891. 44. Amster E, Tiwary A, Schenker MB. Case report: Potential arsenic toxicosis secondary to herbal kelp supplement. Environ Health Perspect. 2007;115:606-608. 45. Bandilla K, Gross D, Gross W. Oral gold therapy with auranofin (SK&F 39162). A multicenter open study in patients with rheumatoid arthritis. J Rheumatol Suppl. 1982;8:154-159. 46. Ross JJ. Shakespeare's chancre: Did the bard have syphilis? Clin Infect Dis. 2005;40:399-404. 47. Senthilkumaran S, Balamurugan N, Vohra R, et al. Paradise nut paradox: Alopecia due to selenosis from a nutritional therapy. Int J Trichology. 2012;4:283-284. 48. Finner AM. Nutrition and hair: Deficiencies and supplements. Dermatol Clin. 2013;31:167-172. 49. Jung S, Oh SJ, Hoon Koh S. Hair follicle transplantation on scar tissue. J Craniofac Surg. 2013;24:1239-1241. 50. Sheng X, Zhang S, Peter Boergen K, et al. Oliver-McFarlane syndrome in a Chinese boy: Retinitis pigmentosa, trichomegaly, hair anomalies and mental retardation. Ophthalmic Genet. 2013. [epub ahead of print]. 51. Opitz JM. 50 years ago in the journal of pediatrics: The cornelia de lange syndrome. J Pediatr. 2013;163:1395. 52. Toro J, Turner M, Gahl WA. Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene. Arch Dermatol. 1999;135:774-780. 53. Mansour AM, Bitar FF, Traboulsi EI. Ocular pathology in congenital heart disease. Eye (Lond). 2005;19:29-34. 54. Bianca S, Bianca M, Ingegnosi C. Reply to ocular pathology in congenital heart disease. Eye (Lond). 2005;19:1340-1341. [author reply 1341]. 55. Paul LJ, Cohen PR, Kurzrock R. Eyelash trichomegaly: Review of congenital, acquired, and drug-associated etiologies for elongation of the eyelashes. Int J Dermatol. 2012;51:631-646.
226 56. Droubi D, Nazareth MR, Rothman IL. Long-term follow-up of previously reported case of trichomegaly associated with alopecia areata in a 3-year-old girl. Pediatr Dermatol. 2012;29:234-235. 57. Santiago M, Travassos AC, Rocha MC, et al. Hypertrichosis in systemic lupus erythematosus (SLE). Clin Rheumatol. 2000;19:245-246. 58. Sharma RC, Mahajan VK, Sharma NL, et al. Trichomegaly of the eyelashes in dermatomyositis. Dermatology. 2002;205:305. 59. Sud N, Shanker V, Sharma A, et al. Mucocutaneous manifestations in 150 HIV-infected Indian patients and their relationship with CD4 lymphocyte counts. Int J STD AIDS. 2009;20:771-774. 60. Vélez A, Kindelán JM, García-Herola A. Acquired trichomegaly and hypertrichosis in metastatic adenocarcinoma. Clin Exp Dermatol. 1995;20:237-239. 61. Möhrenschlager M, Weidinger S, Huss-Marp J. Do gender-specific differences in eyelash length in 5- to 6-year-old preschoolchildren with and without atopic eczema exist? Results from the Miriam study conducted in Augsburg, Germany. Pediatr Dermatol. 2005;22:576-577. 62. Levy Y, Segal N, Ben-Amitai D, et al. Eyelash length in children and adolescents with allergic diseases. Pediatr Dermatol. 2004;21:534-537. 63. Bayer A, Bagkesen H, Sobaci G. Acquired trichomegaly in uveitis. Can J Ophthalmol. 2007;42:101-106. 64. Pucci N, Novembre E, Lombardi E, et al. Long eyelashes in a case series of 93 children with vernal keratoconjunctivitis. Pediatrics. 2005;115:e86-e91. 65. Pucci N, Massai C, Bernardini R, et al. Eyelash length in children with vernal keratoconjunctivitis: Effect of treatment with cyclosporine eye drops. Int J Immunopathol Pharmacol. 2007;20:595-599. 66. Weaver DT, Bartley GB. Cyclosporine-induced trichomegaly. Am J Ophthalmol. 1990;109:239. 67. Tauchi M, Fuchs TA, Kellenberger AJ, et al. Characterization of an in vivo model for the study of eyelash biology and trichomegaly: Mouse eyelash morphology, development, growth cycle, and anagen prolongation by bimatoprost. Br J Dermatol. 2010;162:1186-1197. 68. Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: A five-year review. Support Care Cancer. 2013;21:1167-1174. 69. Ward KM, Barnett C, Fox LP, et al. Eyelash trichomegaly associated with systemic tacrolimus. Arch Dermatol. 2006;142:248. 70. Goksugur N, Karabay O. Eyelash and eyebrow trichomegaly induced by interferon-alfa 2 a. Clin Exp Dermatol. 2007;32:583-584. 71. Howaizi M. Pegylated interferon-induced eyelid and eyebrow trichomegaly during chronic hepatitis C. J Gastroenterol Hepatol. 2005;20: 1945-1946. 72. Hernandez-Nunez A, Fernandez-Herrera J, Buceta LR, et al. Trichomegaly following treatment with interferon alpha-2 b. Lancet. 2002;359:1107. 73. Klutman NE, Hinthorn DR. Excessive growth of eyelashes in a patient with AIDS being treated with zidovudine. N Engl J Med. 1991;324:1896.
A. Vij, W.F. Bergfeld 74. Santmyire-Rosenberger BR, Albert M. Acquired trichomegaly with topiramate. J Am Acad Dermatol. 2005;53:362-363. 75. Shah-Desai S, Sandy C, Collin R. Lax eyelid syndrome or 'progeria' of eyelid tissues. Orbit. 2004;23:3-12. 76. Goldberg RA. Orbicularis muscle aging. JAMA Ophthalmol. 2013;131:94. 77. Nagi KS, Carlson JA, Wladis EJ. Histologic assessment of dermatochalasis: Elastolysis and lymphostasis are fundamental and interrelated findings. Ophthalmology. 2011;118:1205-1210. 78. Kumar M, Singh R. Congenital cutis laxa. Indian Pediatr. 2012;49:771. 79. Mohamed M, Kouwenberg D, Gardeitchik T, et al. Metabolic cutis laxa syndromes. J Inherit Metab Dis. 2011;34:907-916. 80. Kim DP, Klein PA. Acquired cutis laxa in a 55-year-old female with multiple myeloma and serologic evidence of systemic lupus erythematosus. Dermatol Online J. 2011;17:8. 81. Silveira L, Torres I, Salvino MA, et al. Acquired cutis laxa with an interstitial granulomatous reaction associated with IgG lambda monoclonal gammopathy. Am J Dermatopathol. 2013;35:e67-e71. 82. Gray PE, Bock V, Ziegler DS, et al. Neonatal Sweet syndrome: A potential marker of serious systemic illness. Pediatrics. 2012;129: e1353-e1359. 83. Na SY, Choi M, Kim MJ, et al. Penicillamine-induced Elastosis Perforans Serpiginosa and Cutis Laxa in a Patient with Wilson's Disease. Ann Dermatol. 2010;22:468-471. 84. Berk DR, Bentley DD, Bayliss SJ, et al. Cutis laxa: A review. J Am Acad Dermatol. 2012;66:842.e1-842.e17. 85. Appiah YE, Onumah N, Wu H, et al. Multiple myeloma-associated amyloidosis and acral localized acquired cutis laxa. J Am Acad Dermatol. 2008;58:S32-S33. 86. Dicker TJ, Morton J, Williamson RM, et al. Myeloma-associated systemic amyloidosis presenting with acquired digital cutis laxa-like changes. Australas J Dermatol. 2002;43:144-146. 87. Parapia LA, Jackson C. Ehlers-Danlos syndrome–a historical review. Br J Haematol. 2008;141:32-35. 88. Braakenburg A, Nicolai JP. Bilateral eyelid edema: Cutis laxa or blepharochalasis? Ann Plast Surg. 2000;45:538-540. 89. Tsuji T, Imajo Y, Sawabe M. Acquired cutis laxa concomitant with nephrotic syndrome. Arch Dermatol. 1987;123:1211-1216. 90. Anagnostis P, Adamidou F, Poulasouchidou M, et al. Severe eyelid oedema in Graves' ophthalmopathy. BMJ Case Rep. 2013. [pii]. 91. Hallahan KM, Sood A, Singh AD. Acute episode of eyelid oedema. Blepharochalasis. Br J Ophthalmol. 2012;96:909-913. 92. Collin JR. Blepharochalasis. A review of 30 cases. Ophthal Plast Reconstr Surg. 1991;7:153-157. 93. Tehra KG, Kamble M. Self-induced blepharochalasis in a case of facial palsy. Indian J Ophthalmol. 1977;24:33-34. 94. Kumar A, Karthikeyan K. Madarosis: A marker of many maladies. Int J Trichology. 2012;4:3-18.
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis☆ Alok Vij, MD ⁎, Wilma F. Bergfeld, MD Department of Dermatology and Dermatopathology, Cleveland Clinic Foundation, 9500 Euclid Ave, Desk A61, Cleveland, OH 44195, USA
Abstract Eyebrows, eyelashes, and eyelids are cosmetically and functionally important periocular landmarks that offer insights into a patient’s emotional state. Several pathologies exist with respect to the eyebrows, eyelashes, and eyelids. Madarosis refers to loss of the eyebrows or eyelashes; milphosis refers specifically to eyelash loss. Excess growth of eyelash hair is termed trichomegaly. Excess skin in the upper or lower eyelids is called dermatochalasis. Pathology of these important structures can be reflective of important local and systemic disease processes. © 2015 Published by Elsevier Inc.
Anatomy The eyebrows are arched eminences of hair-bearing skin above the eyes which give shape and character to an individual’s face, in addition to protecting the eyes from sweat.1 Eyelashes protect the globe from irritants and foreign bodies through their stimulation of the closing reflex.2 Fibers of several muscles of facial expression insert into the skin underlying the eyebrow, allowing for changes in contour to reflect inner emotions (Figure 1).3 Each eyebrow hair is short and stiff, growing at an angle from the line of the brow.4 The diameter of the hairs can be thicker, as in Caucasians, or thinner, as in Asians, than scalp
☆
All images have been de-identified, except in case of a signed consent form allowing publication of images on file in the Department of Dermatology of the Cleveland Clinic Foundation. ⁎ Corresponding author. Tel.: + 1 2164442651; fax: + 1 2166365151. E-mail address: [email protected] (A. Vij). http://dx.doi.org/10.1016/j.clindermatol.2014.10.013 0738-081X/© 2015 Published by Elsevier Inc.
hair.5,6 The brow can be divided into thirds: medially, lying below the orbital margin with vertical hair growth; the midportion, along the orbital margin with oblique to horizontal growth; and lateral, above the orbital margin, with horizontal growth. Hair density thins from medial to lateral, so organic hair loss is often more apparent laterally.7 Eyelash hairs originate anterior to the palpebral muscle and are set obliquely. The denser upper eyelashes curve upward, while the lower lashes close downward; this prevents interlacing while the eye is closed.4 Eyelash hairs are oval in all races and universally lack arrector pili muscles. Eyelash hairs of Asians are fewer but thicker and with less curvature than those of Caucasians.8 The eyelids are bilamellar structures, with anterior and posterior lamellae.9 The anterior lamella consists of skin and the loosely adherent orbicularis oculi muscle, which can be divided into pretarsal, preseptal, and orbital segments. The pretarsal orbicularis is fixed to the tarsal plate of both upper and lower eyelids. The posterior lamella is composed of the tarsal plate and the conjunctiva. The tarsal plate provides
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Fig. 1
Surface anatomy of the eyebrows and eyelashes.
structural support to the eyelid. The conjunctiva is a stratified squamous nonkeratinizing epthielial layer, which is the most posterior layer of the eyelid (Figure 2).10
Eyebrow and eyelash loss Milphosis and madarosis can be a presenting or associated sign of many diseases. Table 1 includes a broad differential diagnosis for madarosis, sorted by ophthalmologic, dermatologic, and systemic disease. Ophthalmologic causes of milphosis include infectious and inflammatory forms of blepharitis. One effective classification of blepharitis differentiates between anterior and posterior forms based on the location of the inflamma-
Fig. 2 Cross sectional anatomy of the eyelid. The skin and orbicularis make up the anterior lamella; the tarsal plate and conjunctiva make up the posterior lamella.
tion related to the gray line, which separates the skin and muscle (anterior) from the tarsal plate and conjunctiva (posterior). Anterior blepharitis, which may present with presents with itching, burning, tearing, foreign body sensation, and photophobia, can be caused by staphylococcal, seborrheic, and Demodex-related etiologies; posterior blepharitis, presenting with a “foamy” tear film or plugging of the Meibomian orifices, may be caused by any form of Meibomian gland dysfunction.11 Staphylococcal infection usually presents with collarettes, which are hard scales found surrounding and fixed to individual lashes.12 Seborrhea presents with a greasy scale crust also called scruff. Infestation with Demodex folliculorum presents with sleeves, cyclindrical scales connected to the lash root.13,14 Hair loss from any of these causes results from persistent follicular inflammation, rubbing, or secondary infection. It may be scarring or nonscarring. Rosacea-related posterior blepharitis presents with telangiectasia at the eyelid margin and may include other signs or symptoms of rosacea, such as facial flushing, acneiform papules, or phymatous change of the forehead, nose, and chin. If inflammation extends to the anterior lid margin, milphosis may occur (Figure 3).15 Many dermatologic causes of eyebrow and eyelid loss exist, many of which are discussed elsewhere in this series. Atopic dermatitis classically includes “Hertoghe’s sign,” loss of the lateral third of the eyebrows from constant rubbing and scratching,16 in addition to a Dennie Morgan fold, an infraorbital fold due to lower lid edema.17 Seborrheic dermatitis is another pruritic dermatosis that may induce madarosis due to persistent perifollicular inflammation as well as manipulation (Figure 4).18 Hair loss from follicular mucin deposition can result from a malignant inflammatory process, such as cutaneous T-cell lymphoma,19 or as a component of other neoplastic or inflammatory conditions.20 Classically, the lymphomatous follicular mucinosis consists of indurated, waxy plaques of the eyebrows and forehead, although any hair-bearing site may be involved (Figure 5). Persistent contact dermatitis may also induce hair loss; allergic etiologies predominate over irritant in relation to eyelid dermatitis. Frequent allergens include fragrance, metals, and topical antibiotics.21 Psoriatic plaques involving the eyebrow and eyelid are found in approximately 4-10% of patients.22
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis Table 1
Differential diagnosis for madarosis
System
Category
Differential Diagnosis
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Table 1 (continued) System
Ophthalmologic Infectious
Dermatologic
Systemic diseases
Staphylococcal blepharitis Demodex folliculorum blepharitis Trachoma Inflammatory Seborrheic blepharitis Rosacea blepharitis Posterior blepharitis Papulosquamous Atopic dermatitis disorders Contact dermatitis Seborrheic dermatitis Psoriasis Lichen planus Sclerotic Linear scleroderma disorders (en coup de sabre) Parry-Romberg syndrome Sclerodermoid graftversus-host disease Disorders of Lamellar ichthyosis keratinization Monilethrix Hair shaft disorders Pili torti Inflammatory Frontal fibrosing alopecia hair disorders Graham-Little-PiccardiLasseur syndrome Alopecia areata Ulerythema ophyrogenes NonTelogen effluvium inflammatory hair disorders Anagen effluvium Trichotillomania Bullous disease Epidermolysis bullosa Pemphigus foliaceus Other Rosacea Follicular mucinosis Sarcoidosis Erythema multiforme Familial acanthosis nigricans Infectious Leprosy
Category
Tuberculosis (lupus vulgaris) Secondary or tertiary syphilis Erysipelas Folliculitis or furunculosis Trichodysplasia spinulosa Herpes simplex or zoster HIV Molluscum contagiosum Dermatophytes: Trichophyton, Microsporum
Endocrine
Autoimmune disease
Neoplasia Neoplasia
Drugs
Toxic
Nutritional
Trauma
Adapted.92
Differential Diagnosis Deep Fungal: Coccidiomycosis, Paracoccidiomycosis Phthriasis Hypothyroidism Hyperthyroidism Hypoparathyroidism Hyperparathyroidism Hypopituitarism Sheehan's syndrome Amyloidosis Discoid lupus Vogt Koyanagi Harada syndrome Sebaceous carcinoma Squamous cell carcinoma Basal cell carcinoma, Sclerosing sweat duct carcinoma, Leukemia cutis Cutaneous lymphoma Seborrheic keratosis Leiomyoma Mastocytoma Anti-thyroid drugs Anticoagulants Lipid lowering agents Propranolol Valproate Barbiturates Bromocroptine Immunosuppressants Systemic retinoids Chemotherapies MMR vaccination Epinephrine Botulinum toxin Quinine Gold Hypervitaminosis A Thallium Arsenic Bismuth Mercury Biotin deficiency Iron deficiency Zinc deficiency Hypoproteinemia Marasmus Radiation injury Tattoo Physical, chemical, or thermal injuries
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Fig. 3 A 39-year-old patient with granulomatous rosacea of the eyelids, resulting in partial milphosis of both upper and lower eyelids bilaterally. She had associated telangiectasia of the lid margin, facial flushing, and a foreign body sensation of the eyes.
Many inflammatory and noninflammatory causes of hair loss can affect the eyebrows and eyelashes as well as the scalp. Frontal fibrosing alopecia, a clinical variant of lichen planopilaris classically affecting postmenopausal women, is a form of scarring alopecia that results in loss of frontal hairline and eyebrows (Figure 6).23 Additionally, GrahamLittle-Piccardi-Lasseur syndrome consists of lichen planopilaris of the scalp with nonscarring loss of the eyebrows, eyelashes, axillary, and pubic hair.24 Lichen planopilaris is marked by perifollicular keratotic scale and erythema.25 Alopecia areata is an incompletely understood entity thought to be mediated by autoimmune damage after loss of the immune privilege of the follicular unit.26 Alopecia areata is marked by “exclamation point hairs,” tapering as they approach a smooth, bald patch of the scalp, which may have a peach to yellowish hue. Alopecia areata may affect the eyebrows or eyelashes as an isolated finding, with patchy scalp involvement, or as a part of alopecia universalis
Fig. 4 A patient with seborrheic dermatitis and erythemotelangiectatic rosacea. Due to persistent inflammation, his lateral eyebrows were lost. His eyebrows did recover after sufficient treatment of his dermatitis.
A. Vij, W.F. Bergfeld
Fig. 5 Alopecia mucinosa, or follicular mucinosis due to cutaneous T cell lymphoma, of the temporal scalp and eyebrow more than eyelashes. This patient had prominent CD-30 positivity within the lymphomatous infiltrate, and was responded well to brentuximab vedotin; however, she never regrew hair within the alopecic plaques.
(Figure 7). When localized to the eyebrows, there is rarely involvement of other areas of the body.27 The most common form of hair loss is telogen effluvium, marked by shedding of an extraordinarily high percentage of otherwise normal telogen hairs. Usually brought on by acute systemic disease, surgery, emotional stress, or other severe changes in normal physiology, it may result in diffuse thinning of eyebrows and eyelashes in addition to scalp hair.28 Anagen effluvium may be induced by cytotoxic chemotherapies, resulting in decreased hair density globally.29 Trichotillomania and other neurodermatoses may result in picking, plucking, or otherwise manipulating the eyebrows and eyelashes in response to external stressors (Figure 8); these actions may occur in concert with co-morbid psychiatric illness or as an isolated stress-response phenomenon.30
Fig. 6 Frontal fibrosing alopecia. Note the band-like alopecic plaque of the frontal hair line, which has been replaced by an atrophic, shiny white plaque with lonely hair fibers. The patient presented with intact eyebrows, but her inflammatory alopecia eventually caused bilateral madarosis (seen here with makeup).
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis
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Fig. 7 Madarosis of the eyebrows and eyelashes in a patient with alopecia universalis.
In addition to local ophthalmologic and dermatologic causes of hair loss, systemic diseases can have a major effect on hair density of the eyebrows and eyelashes. Infections of all etiologies can impact the eyelashes and eyebrows. Classic “leonine facies” of advanced leprosy include bilateral eyebrow loss,31 but lupus vulgaris is another mycobacterial infection that may induce hair loss32; secondary and tertiary syphilis may result in patchy hair loss of the eyelashes or eyebrows as well as the scalp.33 Many bacterial, viral, and fungal diseases may also thin or obliterate the hairy periocular structures (Figure 9). Many endocrinopathies may cause madarosis as well. Perhaps the most well-known association links hypothyroidism with loss of the lateral third of the eyebrows; this has been coined “Queen Anne’s sign,” after the Danish Queen’s thin eyebrows and suspected goiter.34 Hyperthyroidism, which may induce increased brittleness of the hair, may present with thin, broken off eyelashes.35 Discoid lupus may present with scarring alopecia and dyspigmentation of any hair bearing site (Figure 10). Scleroderma, particularly the linear variant in children, known as “en coup de sabre,” can present with poliosis, localized whitening of the hairs, before circumscribed madarosis within an advancing, sclerotic plaque (Figure 11).36 Its craniofacial counterpart, Parry Romberg
Fig. 8 Madarosis of the mid-portion of the lateral brow and eyelashes in a patient with trichotillomania. Note the coarse terminal hairs growing back within the alopecic patches which were too short for the patient to pluck.
Fig. 9 A patient with zoster ophthalmicus with obliteration of the left eyebrow within the involved dermatome.
syndrome, consists of central nervous system disturbances, including seizures, with hemifacial atrophy and loss of pilosebaceous units.37 Sclerodermoid graft-versus-host disease may induce the same changes.38 Benign and malignant neoplastic conditions may obliterate hairs by direct extension (Figure 12). Medication induced hair loss may be first noticed in the brows and lashes. Among dermatologic drugs, steroid-sparing immunosuppressants like methotrexate,39 mycophenolate mofetil,40 and azathioprine41 may all induce hair loss; hair loss can be a doselimiting side effect of the systemic retinoids acitretin, etretinate, isotretinoin, and bexarotene.42 Hypervitmainosis A, along the same lines, is associated with hair loss,43 as are toxic levels of arsenic,44 gold,45
Fig. 10 A patient with systemic lupus erythematosus with discoid cutaneous lesions. Her left eyebrow has an alopecic patch due to her chronic cutaneous lupus. Note the hyperpigmentation, hypopigmentation, scarring, and atrophy within the involved plaques.
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A. Vij, W.F. Bergfeld Table 2
Differential diagnosis for eyelash trichomegaly
Type
Frequency
Congenital
Common
Acquired
Fig. 11 A patient with “en coup de sabre,” a form of linear scleroderma involving the frontal scalp and forehead. He had stable madarosis of the left eyebrow despite softening of the sclerotic plaque of his forehead with methotrexate.
mercury,46 and selenium.47 Functional deficiency of biotin, iron, and zinc as well as protein and total calorie malnutrition are associated with hair loss.48 Finally, locally destructive scarring processes can prevent hair regrowth.49
Medicationinduced
Fig. 12 Squamous cell carcinoma involving both eyelids and the periorbit. Note the loss of lateral lower eyelashes, resulting from invasive tumor disrupting the follicular units.
Cornelia de Lange syndrome Oliver-McFarlane syndrome Uncommon Congenital heart disease Familial trichomegaly Hermansky-Pudlak syndrome Rare Aghaei-Dastgheib syndrome Cone-rod dystrophy Goldstein-Hutt syndrome Phylloid hypomelanosis Common Atopic dermatitis HIV infection Uveitis Vernal conjuntivitis Rare Alopecia areata Dermatomyositis Malignancy Systemic lupus erythematosus Frequent Prostaglandin analogs Common
Cetuximab Erlotinib Uncommon Gefitinib Panitumumab Interferon alpha Rare Cyclosporine Tacrolimus Topiramate Zidovudine
Eyelash trichomegaly Eyelash trichomegaly is defined as eyelashes which are increased in length, thickness, and pigmentation. Trichomegaly may appear congenitally as a familial trait or in association with a genetic syndrome; it may be an acquired finding which may be a sign of immune dysfunction or accompany treatment with a local or systemic medication. Table 2 offers a differential diagnosis for trichomegaly.
Differential Diagnosis
Adapted.53
Many congenital syndromes may have trichomegaly as a rare feature, but only two, Oliver-McFarlane syndrome and Cornelia de Lange syndrome, count eyelash trichomegaly as a defining diagnostic criterion. Oliver-McFarlane syndrome is a rare autosomal recessive syndrome, with affected patients having retinal pigment degeneration, dwarfism, and mental retardation that may exist in association with hypothyroidism, hypogonadism, or growth hormone deficiency.50 Cornelia de Lange syndrome includes eyelash trichomegaly in association with small stature and malformations of the musculoskeletal, cardiac, neurologic, and gastrointestinal systems. The patients have characteristic facies, including high, arched eyebrows that meet in the midline (synophris) and extend down the nasal bridge; dysplastic, low set ears; short nose with depressed nasal bridge and long, prominent philtrum; thin upper lip; downturned oral commissures; and flattened midface.51 Other clinical syndromes frequently present with trichomegaly, but this finding is not required for diagnosis. Hermansky-Pudlak syndrome frequently has trichomegaly; this syndrome consists of oculocutaneous albinism and a
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis Table 3
223
Congenital syndromes with hypertrichosis of the eyelashes and associated features
Syndrome
Associated Features
Aghaei-Dastgheib syndrome Cone-rod dystrophy Cornelia de Lange syndrome Goldstein-Hutt syndrome Hermansky-Pudlak syndrome Oliver-McFarlane syndrome Phylloid hypomelanosis
Generalized hypertrichosis, bilateral nipple retraction, accessory nipple Cone-rod amaurosis, hypertrichosis Synophrys, facial and musculoskeletal anomalies, small stature, developmental delay Cataracts, hereditary spherocytosis Oculocutaneous albinism, platelet storage pool deficiency, ceroid lipofuscin accumulation Pigmentary retinal degeneration, dwarfism, mental retardation Hypopigmented macules; chromosome 13 q anomalies; cerebral, ocular, and skeletal defects
Adapted.53
bleeding diathesis related to an absence of platelet dense bodies. Additionally, accumulation of ceroid lipofuscin in lysosomes is thought to lead to pulmonary fibrosis, often fatal, and granulomatous colitis.52 Congenital trichomegaly may present in infants with congenital heart disease; this association was initially attributed to high degrees of parental consanguinity, although recent reports have brought that association into question.53,54 Many other syndromes have been described in which rare reports of trichomegaly exist. These have been well classified elsewhere, and are presented in Table 3.55 As with congenital conditions, eyelash trichomegaly may occur commonly or rarely in concert with local cutaneous, ophthalmologic, or systemic disease processes. Eyelash trichomegaly has rarely been reported in alopecia areata,56 autoimmune connective tissue diseases like systemic lupus erythematosus57 and dermatomyositis,58 HIV infection,59 and malignancies.60 Frequently, patients with atopic diseases such as atopic dermatitis61 and allergic rhinitis62 may have acquired
trichomegaly. Uveitis of any cause is associated with a statistically significant increased eyelash length compared to age- and sex-matched controls. This finding is thought to be mediated by local alterations of cytokine and growth factor expression.63 Vernal keratoconjunctivitis, bilateral allergic conjunctivitis, is associated with longer upper eyelashes, the length of
Fig. 13 Panel A, Eyelashes of a patient before starting topical bitamoprost. Panel B, Eyelashes of a patient after using topical bitamoprost daily for 6 months.
Fig. 14 Panel A, Acute episode of eyelid edema in a patient with blepharochalasis. Panel B, Redundant and lax skin of the lower eyelid as a consequence of serial episodes of profound edema.
224 Table 4
A. Vij, W.F. Bergfeld Differential diagnosis for dermatochalasis
Normal changes of aging Lax eyelid syndrome Congenital Cutis Laxa Ehlers-Danlos syndrome Plasma cell dyscrasia Amyloidosis Systemic Lupus Erythematosus Sweet’s syndrome Penicillamine therapy Blepharochalasis
which positively correlate to symptoms. Trichomegaly may be a multifactorial compensatory mechanism, induced to increase local defenses to exacerbating factors of sun, wind, and foreign particles.64 Treatment with cyclosporine eye drops was associated with decreased eyelash length in patients with vernal keratoconjunctivitis.65 This finding contrasts with the known association of cyclosporine treatment inducing eyelash trichomegaly.66 Many medications have been associated with trichomegaly. Topical prostaglandins, for instance, so regularly and reliably produce trichomegaly that they are now offered as cosmetic treatments to enhance eyelash appearance (Figure 13). 67 Epidermal growth factor receptor inhibitors have become commonly used oncologic treatments due to their safety with good antitumor activity against a broad range of epithelial carcinomas. Cetuximab and panitumumab are monoclonal antibodies which inhibit the aberrant epidermal growth factor receptor expression extracellularly; erlotinib and gefitinib are small molecule tyrosine kinase inhibitors intracellularly interrupt the same signal transduction pathway. Cetuximab and erlotinib more commonly induce eyelash trichomegaly than panitumumab and gefitinib.68 Immunomodulatory medications as well may induce trichomegaly. Eyelash trichomegaly may occur in the minority of patients treated with systemic cyclosporine and tacrolimus69; rarer still is the induction of trichomegaly with various interferons.70–72 The antiretroviral medication zidovudine73 and the antiepileptic medication topiramate74 rarely cause eyelash trichomegaly as well.
Histopathological studies indicate that atrophy of the epidermis and dermis are responsible for the sagging eyelids, with preservation of the orbicularis oculi muscle.76 The most characteristic findings included loss of elastic fibers, widened spacing between collagen bundles, and dilation of lymph vessels with resultant lymphedema. 77 These histologic findings may occur simply as a consequence of the aging process, but they also correlate with the major pathologic changes found in syndromic variants of dermatochalasis. The most common syndromic cause of dermatochalasis is cutis laxa, which can itself be a hereditary disease or an acquired condition. Cutis laxa is characterized by wrinkled, inelastic, redundant skin due to defects in the elastic fibers or other molecules of the extracellular matrix; when the eyelids are involved, dermatochalasis is the result. The hereditary form of cutis laxa can be associated with a number of systemic findings,78 or it can be associated with a number of metabolic diseases.79 Acquired cutis laxa has been reported in concert with plasma cell dyscrasia with80 or without81 systemic lupus erythematosus, as a postinflammatory change in Sweet’s syndrome,82 and as a result of penicillamine therapy,83 among others.84 Amyloidosis is also thought to be a risk factor for dermatochalasis, although its association with acquired cutis laxa obscures a potential direct relationship.85,86 EhlersDanlos Syndrome, a heterogenous group of inherited defects of collagen, may predispose to dermatochalasis.87 Angioedema has been reported to cause dermatochalasis,88 most likely as an end-stage result from multiple bouts of extreme edema, resulting in altered lymphatic drainage. Persistent edema from nephrotic syndrome89 or thyroid orbitopathy90 may induce similar changes. Blepharochalasis is a rare, idiopathic disease characterized by recurrent episodes of acute eyelid edema (Figure 14), resulting eventually in lax, atrophic skin.91–93 Self-induced trauma has been reported to cause blepharochalasis.94
Conclusions In addition to giving insight to an individual’s emotional state, the periocular structures can provide a wealth of information to a host of local and systemic disease states. Careful observation is required to take note of changes of the eyebrows, eyelashes, and eyelids. A wide differential exists for changes in these structures.
Dermatochalasis Dermatochalasis most commonly affects the elderly, although it can present as early as 40 in acquired cases and 20 in congenital cases. Redundant skin may predispose to loss of the superior visual field or may cause upper eyelid entropion or lower eyelid ectropion or retraction. Acquired forms of dermatochalasis in younger individuals without systemic associations has been termed the lax eyelid syndrome, akin to a localized progeria of the eyelids.75 See Table 4 for a differential diagnosis for dermatochalasis.
References 1. Margulis A, Amar D, Billig A, et al. Periorbital reconstruction with the expanded pedicled forehead flap. Ann Plast Surg. 2013. [epub ahead of print]. 2. Hwang K. Surgical anatomy of the upper eyelid relating to upper blepharoplasty or blepharoptosis surgery. Anat Cell Biol. 2013;46:93-100. 3. Kikkawa DO, Lemke BN, Dortzbach RK. Relations of the superficial musculoaponeurotic system to the orbit and characterization of the orbitomalar ligament. Ophthal Plast Reconstr Surg. 1996;12:77-88.
Madarosis, milphosis, eyelash trichomegaly, and dermatochalasis 4. Epstein J. Facial hair restoration: Hair transplantation to eyebrows, beard, sideburns, and eyelashes. Facial Plast Surg Clin North Am. 2013;21:457-467. 5. Price KM, Gupta PK, Woodward JA, et al. Eyebrow and eyelid dimensions: An anthropometric analysis of African Americans and Caucasians. Plast Reconstr Surg. 2009;124:615-623. 6. Kunjur J, Sabesan T, Ilankovan V. Anthropometric analysis of eyebrows and eyelids: An inter-racial study. Br J Oral Maxillofac Surg. 2006;44:89-93. 7. Haddad D, Gemperli R. Surgical correction of aesthetically deformed eyebrows using local transposition flaps. Aesthetic Plast Surg. 2010;34: 734-737. 8. Na JI, Kwon OS, Kim BJ, et al. Ethnic characteristics of eyelashes: A comparative analysis in Asian and Caucasian females. Br J Dermatol. 2006;155:1170-1176. 9. Codner MA, Hanna MK. Applied anatomy of the eyelids and orbit. In: Nahai F, ed. The Art of Aesthetic Surgery: Principles and Techniques. St. Louis, MO: Quality Medical Publishing; 2005. p. 625-650. 10. Alghoul M, Pacella SJ, McClellan WT, et al. Eyelid reconstruction. Plast Reconstr Surg. 2013;132:288 e-302 e. 11. Lindsley K, Matsumura S, Hatef E, et al. Interventions for chronic blepharitis. Cochrane Database Syst Rev. 2012;5:CD005556. 12. O’Brien TP. The role of bacteria in blepharitis. Ocul Surf. 2009;7: S21-S22. 13. Jackson WB. Blepharitis: Current strategies for diagnosis and management. Can J Ophthalmol. 2008;43:170-179. 14. Hom MM, Mastrota KM, Schachter SE. Demodex. Optom Vis Sci. 2013;90(7):e198-e205. 15. Vieira AC, Hofling-Lima AL, Mannis MJ. Ocular rosacea—a review. Arq Bras Oftalmol. 2012;75:363-369. 16. Nagaraja Kanwar AJ, Dhar S, et al. Frequency and significance of minor clinical features in various age-related subgroups of atopic dermatitis in children. Pediatr Dermatol. 1996;13:10-13. 17. Schram MR, Leeflang MM, et al. Validation and refinement of the Millenium Criteria for atopic dermatitis. J Dermatol. 2011;36:850-858. 18. Ishida M, Iwai M, Yoshida K, et al. Adult T-cell leukemia/lymphoma accompanying follicular mucinosis: A case report with review of the literature. Int J Clin Exp Pathol. 2013;6:3014-3018. 19. Mir-Bonafé JM, Cañueto J, Fernández-López E, et al. Follicular mucinosis associated with nonlymphoid skin conditions. Am J Dermatopathol. 2013. [Epub ahead of print]. 20. Dessinioti C, Katsambas A. Seborrheic dermatitis: Etiology, risk factors, and treatments: Facts and controversies. Clin Dermatol. 2013;31:343-351. 21. Amin KA, Belsito DV. The aetiology of eyelid dermatitis: A 10-year retrospective analysis. Contact Dermatitis. 2006;55:280-285. 22. Zhu F, Tao JP. Bilateral upper and lower eyelid severe psoriasiform blepharitis: Case report and review of the literature. Ophthal Plast Reconstr Surg. 2011;27:e138-e139. 23. Lencastre A, Tosti A. Images in clinical medicine. A receding hairline. N Engl J Med. 2013:e2. 24. Laszlo FG. Graham-Little-Piccardi-Lasseur syndrome: Case report and review of the syndrome in men. Int J Dermatol. 2013. [epub ahead of print]. 25. Cevasco NC, Bergfeld WF, Remzi BK, et al. A case-series of 29 patients with lichen planopilaris: The Cleveland Clinic Foundation experience on evaluation, diagnosis, and treatment. J Am Acad Dermatol. 2007;57:47-53. 26. Ito T. Recent advances in the pathogenesis of autoimmune hair loss disease alopecia areata. Clin Dev Immunol. 2013;2013:348546. 27. Finner AM. Alopecia areata: Clinical presentation, diagnosis, and unusual cases. Dermatol Ther. 2011;24:348-354. 28. Bergfeld WF, Mulinari-Brenner F. Shedding: How to manage a common cause of hair loss. Cleve Clin J Med. 2011;68:256-261. 29. Kanwar AJ, Narang T. Anagen effluvium. Indian J Dermatol Venereol Leprol. 2013;79:604-612.
225
30. Bergfeld W, Mulinar-Brenner F, McCarron K, et al. The combined utilization of clinical and histologic findings in the diagnosis of trichotillomania. J Cutan Pathol. 2002;29:207-214. 31. Krishnan A, Kar S. Bilateral madarosis as the solitary presenting feature of multibacillary leprosy. Int J Trichology. 2012;4:179-180. 32. Miteva L. Alopecia: A rare manifestation of lupus vulgaris. Int J Dermatol. 2011;40:659-661. 33. Hernanez-Bel P, Unamuno B, Sanchez-Carazo JL, et al. Syphilitic alopecia: A report of 5 cases and a review of the literature. Actas Dermosifiliogr. 2013;104:512-517. 34. Lane Furdell R. Eponymous, anonymous: Queen Anne’s sign and the misnaming of a symptom. J Med Biogr. 2007;15:97-101. 35. Jordan DR, Ahuja N, Khouri L. Eyelash loss associated with hyperthyroidism. Ophthal Plast Reconstr Surg. 2002;18:219-222. 36. Pierre-Louis M, Sperling LC, Wilke MS, et al. Distinctive histopathologic findings in linear morphea (en coup de sabre) alopecia. J Cutan Pathol. 2013;40:580-584. 37. Borodic GE, Caruso P, Acquardo M, et al. Parry Romberg syndrome vasculopathy and its treatment with Botulinum toxin. Ophthal Plast Reconstr Surg. 2014;30:e22-e25. 38. Nassar A, Tabbara KF, Aljurf M. Ocular manifestations of graft-versushost disease. Saudi J Ophthalmol. 2013;27:215-222. 39. Chan ES, Cronsterin BN. Mechanisms of action of methotrexate. Bull Hosp Jt Dis. 2013;71:5-8. 40. Tse KC, Tang CS, Lio WI, et al. Quality of life comparison between corticosteroid- and-mycofenolate mofetil and corticosteroid- and-oral cyclophosphamide in the treatment of severe lupus nephritis. Lupus. 2006;15:371-379. 41. Sood A, Midha V, Sood N, et al. Long term results of use of azathioprine in patients with ulcerative colitis in India. World J Gastroenterol. 2006;12:7332-7336. 42. Chappell JA, Chu MB, Martin K, et al. Acitretin-induced poliosis with concurrent alopecia. J Drugs Dermatol. 2012;11:247-249. 43. Cheruvattath R, Orrego M, Gautam M, et al. Vitamin A toxicity: When one a day doesn't keep the doctor away. Liver Transpl. 2006;12: 1888-1891. 44. Amster E, Tiwary A, Schenker MB. Case report: Potential arsenic toxicosis secondary to herbal kelp supplement. Environ Health Perspect. 2007;115:606-608. 45. Bandilla K, Gross D, Gross W. Oral gold therapy with auranofin (SK&F 39162). A multicenter open study in patients with rheumatoid arthritis. J Rheumatol Suppl. 1982;8:154-159. 46. Ross JJ. Shakespeare's chancre: Did the bard have syphilis? Clin Infect Dis. 2005;40:399-404. 47. Senthilkumaran S, Balamurugan N, Vohra R, et al. Paradise nut paradox: Alopecia due to selenosis from a nutritional therapy. Int J Trichology. 2012;4:283-284. 48. Finner AM. Nutrition and hair: Deficiencies and supplements. Dermatol Clin. 2013;31:167-172. 49. Jung S, Oh SJ, Hoon Koh S. Hair follicle transplantation on scar tissue. J Craniofac Surg. 2013;24:1239-1241. 50. Sheng X, Zhang S, Peter Boergen K, et al. Oliver-McFarlane syndrome in a Chinese boy: Retinitis pigmentosa, trichomegaly, hair anomalies and mental retardation. Ophthalmic Genet. 2013. [epub ahead of print]. 51. Opitz JM. 50 years ago in the journal of pediatrics: The cornelia de lange syndrome. J Pediatr. 2013;163:1395. 52. Toro J, Turner M, Gahl WA. Dermatologic manifestations of Hermansky-Pudlak syndrome in patients with and without a 16-base pair duplication in the HPS1 gene. Arch Dermatol. 1999;135:774-780. 53. Mansour AM, Bitar FF, Traboulsi EI. Ocular pathology in congenital heart disease. Eye (Lond). 2005;19:29-34. 54. Bianca S, Bianca M, Ingegnosi C. Reply to ocular pathology in congenital heart disease. Eye (Lond). 2005;19:1340-1341. [author reply 1341]. 55. Paul LJ, Cohen PR, Kurzrock R. Eyelash trichomegaly: Review of congenital, acquired, and drug-associated etiologies for elongation of the eyelashes. Int J Dermatol. 2012;51:631-646.
226 56. Droubi D, Nazareth MR, Rothman IL. Long-term follow-up of previously reported case of trichomegaly associated with alopecia areata in a 3-year-old girl. Pediatr Dermatol. 2012;29:234-235. 57. Santiago M, Travassos AC, Rocha MC, et al. Hypertrichosis in systemic lupus erythematosus (SLE). Clin Rheumatol. 2000;19:245-246. 58. Sharma RC, Mahajan VK, Sharma NL, et al. Trichomegaly of the eyelashes in dermatomyositis. Dermatology. 2002;205:305. 59. Sud N, Shanker V, Sharma A, et al. Mucocutaneous manifestations in 150 HIV-infected Indian patients and their relationship with CD4 lymphocyte counts. Int J STD AIDS. 2009;20:771-774. 60. Vélez A, Kindelán JM, García-Herola A. Acquired trichomegaly and hypertrichosis in metastatic adenocarcinoma. Clin Exp Dermatol. 1995;20:237-239. 61. Möhrenschlager M, Weidinger S, Huss-Marp J. Do gender-specific differences in eyelash length in 5- to 6-year-old preschoolchildren with and without atopic eczema exist? Results from the Miriam study conducted in Augsburg, Germany. Pediatr Dermatol. 2005;22:576-577. 62. Levy Y, Segal N, Ben-Amitai D, et al. Eyelash length in children and adolescents with allergic diseases. Pediatr Dermatol. 2004;21:534-537. 63. Bayer A, Bagkesen H, Sobaci G. Acquired trichomegaly in uveitis. Can J Ophthalmol. 2007;42:101-106. 64. Pucci N, Novembre E, Lombardi E, et al. Long eyelashes in a case series of 93 children with vernal keratoconjunctivitis. Pediatrics. 2005;115:e86-e91. 65. Pucci N, Massai C, Bernardini R, et al. Eyelash length in children with vernal keratoconjunctivitis: Effect of treatment with cyclosporine eye drops. Int J Immunopathol Pharmacol. 2007;20:595-599. 66. Weaver DT, Bartley GB. Cyclosporine-induced trichomegaly. Am J Ophthalmol. 1990;109:239. 67. Tauchi M, Fuchs TA, Kellenberger AJ, et al. Characterization of an in vivo model for the study of eyelash biology and trichomegaly: Mouse eyelash morphology, development, growth cycle, and anagen prolongation by bimatoprost. Br J Dermatol. 2010;162:1186-1197. 68. Borkar DS, Lacouture ME, Basti S. Spectrum of ocular toxicities from epidermal growth factor receptor inhibitors and their intermediate-term follow-up: A five-year review. Support Care Cancer. 2013;21:1167-1174. 69. Ward KM, Barnett C, Fox LP, et al. Eyelash trichomegaly associated with systemic tacrolimus. Arch Dermatol. 2006;142:248. 70. Goksugur N, Karabay O. Eyelash and eyebrow trichomegaly induced by interferon-alfa 2 a. Clin Exp Dermatol. 2007;32:583-584. 71. Howaizi M. Pegylated interferon-induced eyelid and eyebrow trichomegaly during chronic hepatitis C. J Gastroenterol Hepatol. 2005;20: 1945-1946. 72. Hernandez-Nunez A, Fernandez-Herrera J, Buceta LR, et al. Trichomegaly following treatment with interferon alpha-2 b. Lancet. 2002;359:1107. 73. Klutman NE, Hinthorn DR. Excessive growth of eyelashes in a patient with AIDS being treated with zidovudine. N Engl J Med. 1991;324:1896.
A. Vij, W.F. Bergfeld 74. Santmyire-Rosenberger BR, Albert M. Acquired trichomegaly with topiramate. J Am Acad Dermatol. 2005;53:362-363. 75. Shah-Desai S, Sandy C, Collin R. Lax eyelid syndrome or 'progeria' of eyelid tissues. Orbit. 2004;23:3-12. 76. Goldberg RA. Orbicularis muscle aging. JAMA Ophthalmol. 2013;131:94. 77. Nagi KS, Carlson JA, Wladis EJ. Histologic assessment of dermatochalasis: Elastolysis and lymphostasis are fundamental and interrelated findings. Ophthalmology. 2011;118:1205-1210. 78. Kumar M, Singh R. Congenital cutis laxa. Indian Pediatr. 2012;49:771. 79. Mohamed M, Kouwenberg D, Gardeitchik T, et al. Metabolic cutis laxa syndromes. J Inherit Metab Dis. 2011;34:907-916. 80. Kim DP, Klein PA. Acquired cutis laxa in a 55-year-old female with multiple myeloma and serologic evidence of systemic lupus erythematosus. Dermatol Online J. 2011;17:8. 81. Silveira L, Torres I, Salvino MA, et al. Acquired cutis laxa with an interstitial granulomatous reaction associated with IgG lambda monoclonal gammopathy. Am J Dermatopathol. 2013;35:e67-e71. 82. Gray PE, Bock V, Ziegler DS, et al. Neonatal Sweet syndrome: A potential marker of serious systemic illness. Pediatrics. 2012;129: e1353-e1359. 83. Na SY, Choi M, Kim MJ, et al. Penicillamine-induced Elastosis Perforans Serpiginosa and Cutis Laxa in a Patient with Wilson's Disease. Ann Dermatol. 2010;22:468-471. 84. Berk DR, Bentley DD, Bayliss SJ, et al. Cutis laxa: A review. J Am Acad Dermatol. 2012;66:842.e1-842.e17. 85. Appiah YE, Onumah N, Wu H, et al. Multiple myeloma-associated amyloidosis and acral localized acquired cutis laxa. J Am Acad Dermatol. 2008;58:S32-S33. 86. Dicker TJ, Morton J, Williamson RM, et al. Myeloma-associated systemic amyloidosis presenting with acquired digital cutis laxa-like changes. Australas J Dermatol. 2002;43:144-146. 87. Parapia LA, Jackson C. Ehlers-Danlos syndrome–a historical review. Br J Haematol. 2008;141:32-35. 88. Braakenburg A, Nicolai JP. Bilateral eyelid edema: Cutis laxa or blepharochalasis? Ann Plast Surg. 2000;45:538-540. 89. Tsuji T, Imajo Y, Sawabe M. Acquired cutis laxa concomitant with nephrotic syndrome. Arch Dermatol. 1987;123:1211-1216. 90. Anagnostis P, Adamidou F, Poulasouchidou M, et al. Severe eyelid oedema in Graves' ophthalmopathy. BMJ Case Rep. 2013. [pii]. 91. Hallahan KM, Sood A, Singh AD. Acute episode of eyelid oedema. Blepharochalasis. Br J Ophthalmol. 2012;96:909-913. 92. Collin JR. Blepharochalasis. A review of 30 cases. Ophthal Plast Reconstr Surg. 1991;7:153-157. 93. Tehra KG, Kamble M. Self-induced blepharochalasis in a case of facial palsy. Indian J Ophthalmol. 1977;24:33-34. 94. Kumar A, Karthikeyan K. Madarosis: A marker of many maladies. Int J Trichology. 2012;4:3-18.
