Clinics in Dermatology (2015) 33, 170–182

Hemangiomas and the eye☆ Allyson A. Spence-Shishido, MD a , William V. Good, MD b , Eulalia Baselga, MD c , Ilona J. Frieden, MD a,⁎ a

Department of Dermatology, University of California-San Francisco School of Medicine, 1701 Divisadero Street, 3rd Floor, San Francisco, CA 94115 b The Smith-Kettlewell Eye Research Institute, 2318 Fillmore Street, San Francisco, CA 94115 c Pediatric Dermatology Section, Department of Dermatology, Hospital de la Santa Creu I Sant Pau, S Antoni M Claret 167, 08025 Barcelona, Spain

Abstract Infantile hemangiomas are a common vascular birthmark with heterogeneous presentations and unique growth characteristics with early rapid growth and eventual self-involution. Hemangiomas that develop around the eye have the potential for inducing amblyopia by several mechanisms and may eventually result in permanent visual impairment in otherwise healthy infants. Segmental periocular hemangiomas carry the additional risk of associated structural anomalies and PHACE syndrome. In recent years, the treatment of periocular hemangiomas has been revolutionized by the serendipitous discovery of the effectiveness of beta-blockers (systemic and topical), with most experts viewing these as first-line therapies. The management of periocular hemangiomas should involve a close partnership between an ophthalmologist and dermatologist or other relevant specialists familiar with the unique clinical features, differential diagnosis, treatment approaches, and potential complications. © 2015 Elsevier Inc. All rights reserved.

Introduction Infantile hemangiomas (IH) are a common birthmark occurring in 4-5% of all infants, with female gender, prematurity, Caucasian race, and multiple gestation pregnancies as risk factors.1–3 Hemangiomas of the head and neck are common,4,5 as is periocular involvement, but the exact incidence is unknown. One retrospective review found that 24.3% of all focal facial hemangiomas involved periocular sites.6 Additional data from the Hemangioma Investigator Group of 1096 consecutively enrolled patients ☆

Drs. Frieden and Baselga disclose that they are consultants for Pierre Fabre. Dr. Baselga is also a principle investigator in the HEMANGIOL study, which was sponsored by Pierre Fabre. ⁎ Corresponding author. Tel.: +1 4153537883; fax: + 1 4153537850. E-mail address: [email protected] (I.J. Frieden). http://dx.doi.org/10.1016/j.clindermatol.2014.10.009 0738-081X/© 2015 Elsevier Inc. All rights reserved.

with ≥ 1 hemangioma at any site,3 found that 12% had a periocular IH (E. Baselga, MD, personal written communication, October 2013). In contrast, a populationbased cohort study estimated that periocular infantile hemangiomas occur in only 1 in 1586 live births, though the authors acknowledge that this may be an underestimate due to the retrospective design and possible incomplete data collection.7 Whatever the true incidence, the periorbital area is a relatively frequent site for IH and a particularly important one, because it can lead to permanent visual loss or distortion of anatomic landmarks in the area. Of the 1096 patients followed by the Hemangioma Investigator Group, 41% suffered some form of visual compromise (E. Baselga, MD, personal written communication, October 2013). The timing of appearance of IH and the timing of its proliferative phase coincides with a critical time in the development of the visual axis, which includes integration of

Hemangiomas and the eye signals received by the retina, and processing the images in the central visual system.8 Abnormal visual development can result in abnormal vision at the level of the central nervous system, which cannot be later corrected as easily by simple intervention, such as the addition of glasses.9 The critical period for the development of the visual axis in humans is thought to be between birth and 9 years of age.8,9 Observation of monocular deprivation in humans suggests that younger age and longer duration of deprivation have more significant effect on vision8; however, studies done in kittens in 1970 revealed that even very brief 3-4 day periods of unilateral eye closure during the first few months of life result in irreversible changes in the visual axis.10 Similarly, early studies in humans showed that even after involution of a periocular hemangioma, associated refractive errors did not always resolve, suggesting permanent effects on the visual axis.11 Given the potential for permanent visual impairment, physicians managing IH need to recognize worrisome clinical features, and be aware of when, and to whom, the patient should be referred. This contribution reviews highlights of pathogenesis, clinical features, potential complications, differential diagnosis, and management options for periocular hemangiomas.

Pathogenesis The pathogenesis of infantile hemangiomas is still incompletely understood. Several excellent recent review contributions have discussed recent advances in our understanding of hemangioma pathogenesis. 12–14 Numerous diverse hypotheses exist, including theories of placental origin, 15,16 somatic gene mutation, 17,18 hypoxia-driven events,19 and aberrant stem cells.20,21 In 2000, it was shown that endothelial cells within infantile hemangiomas are glucose transporter 1 (GLUT1) positive, a unique feature that allowed differentiation of IH from other vascular tumors and malformations.22 GLUT1, an erythrocyte-type glucose transporter protein, is typically expressed on endothelial cells at blood-tissue barriers.22 This group further reported unique similarities in immunoreactivity between endothelial cells of infantile hemangiomas and human placenta (FcγRII, merosin, Lewis Y antigen, and GLUT1). 16 This work led investigators to speculate regarding whether IH represent invasion of the skin with angioblasts destined to produce a placental phenotype or direct embolization of placental cells to the skin and other affected organs.16 Further work has demonstrated genetic similarity between the placenta and hemangioma.15 This hypothesis is most intriguing and attractive as it may explain the unique natural history of the infantile hemangioma, with rapid proliferation, followed by slow self-involution, similar to the 9-month life cycle of the human placenta.15,16 Another proposed theory suggests a role for hypoxia in the pathogenesis of hemangiomas.19 GLUT1, in fact, plays

171 an important role in cellular response and survival in hypoxic environments.23,24 Additionally, infantile hemangiomas are remarkably similar to retinopathy of prematurity, another disorder of abnormal vascular proliferation thought to be related to hypoxia.25 Both present exclusively in the perinatal period, are more common in premature and low birth-weight infants, have similar histopathologic features, undergo early proliferation followed by later involution, and are GLUT1 positive.19,26 Interestingly, premature infants with infantile hemangiomas have been found to be more likely to have retinopathy of prematurity than those without hemangiomas.27

Clinical features and potential complications Growth characteristics IH have a characteristic and well-documented natural history: up to 65% of infants with superficial IH have a precursor sign at birth28 (telangiectatic patches with a pale halo, erythematous patches, pale patches, bruise-like macules) followed by rapid proliferation, then slow involution.2,29 Hemangiomas grow most rapidly in the first 3.2 months of life, reaching an average of 80% of their final size during this time.30 During these first 3 months of life, IH growth is most rapid between 5.5 and 7.5 weeks.28 After this rapid growth, hemangiomas slowly involute. It was previously thought that 30% of hemangiomas regress by 3 years, and 76% by 7 years31; however, newer data suggest that involution is completed much earlier, by age 3 or 4.32,33 Compared to superficial hemangiomas, deep hemangiomas typically begin their growth phase about 1 month later and continue growing 1 month longer.30 Features that predict prolonged growth include deep component, segmental pattern, and orbital involvement.34,35 Although virtually all IH eventually involute spontaneously, they can be associated with significant complications during the proliferative phase. Additionally, even after involution, periocular hemangiomas can leave potentially permanent visual impairment, as well as permanent skin changes, including telangiectasia, scarring, anetoderma, or fibrofatty residua (Figure 1).

Classification Periorbital hemangiomas may be classified based on their depth of skin involvement as superficial (Figure 2), deep (Figures 3 and 4), or mixed (ie, superficial and deep, Figures 5 and 6). Another common way of describing hemangiomas (which is also very useful for risk-stratification) is localized, segmental, and indeterminate.5,36 Localized hemangiomas are those that are spatially confined and appear to arise from a central focus; segmental hemangiomas (Figure 7) are those that encompass a territory of skin such as a developmental segment or portion thereof; and indeterminate hemangiomas (Figure 8) are those that cannot easily be classified into these two descriptions.36

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Fig. 3 Deep hemangioma on the upper eyelid causing ptosis and visual axis obstruction. This type of IH requires urgent intervention to prevent permanent visual sequelae.

Fig. 1 Panel A, Evolution of a localized hemangioma from birth to 4 months of age. Panel B, Same patient at 3 months, and panel C, 1 year. Despite initiation of systemic therapy with propranolol at 3 months, residual telangiectasia and fibrofatty skin changes ultimately requiring surgical intervention had already occurred. Reproduced with permission from Pediatrics, Vol. 130, Pages e314–e320, Copyright 2012 by the AAP.

Periocular hemangiomas can further be classified by their location within and surrounding the orbit. Hemangiomas can be confined to the eyelid (anterior to the globe), extraconal (behind the bony orbit, but outside the extraocular muscles), or intraconal (within the cone of the extraocular muscles).37 Hemangiomas may involve the conjunctiva either as isolated lesions (rare)12,38 or in association with other periocular IH (reportedly found in over one-third of patients).39 There have also been rare cases of IH involving other ocular sites, such as the iris.40–42 Organogenesis of the eye begins during the fourth week of gestation43 with ventral emergence of the orbit and its associated structures.5 Although the classification of localized versus segmental was characterized based on skin characteristics, applying these concepts to orbital hemangiomas would imply that those with intraconal involvement would be classified as segmental as they arise in a developmental segment, rather than as a localized spatially-confined growth.

Potential complications Periocular hemangiomas can permanently affect vision by causing amblyopia, also known as a “lazy eye”44 (See Table 1

Fig. 2 Superficial hemangiomas. Panel A, Superficial IH on left upper eyelid, b 1 cm in diameter. Panel B, Superficial IH right lateral lower eyelid, distant from the eyelid margin. Panel C, Superficial IH left lower eyelid with minimal progressive growth documented over 2 months. Because of their size, these hemangiomas are unlikely to cause permanent visual sequelae, but must be monitored closely through the growth phase to ensure that no development of vision-threatening features ensues.

Hemangiomas and the eye

Fig. 4 Deep hemangioma involving the left orbit with associated ptosis but without overlying epidermal change. In addition to evaluation by an ophthalmologist, radiologic imaging should be considered to confirm diagnosis.

for useful ophthalmologic definitions). Amblyopia is caused by abnormal/suppressed visual axis development (both eye and brain) due to abnormal images received from one eye, and is the most common preventable cause of monocular childhood blindness in the United States.44 IH can result in amblyopia by three mechanisms: (1) direct pressure on the globe induces astigmatism or myopia causing an asymmetric refractive error between the two eyes (anisometropia)9,44; (2) partial or complete occlusion of the visual axis9,45; and (3) induction of strabismus (misalignment of the eyes) due to hemangioma mass effect or by involvement of the extraocular muscles.9 Of these, the first mechanism is far more common than the others.9 Optic nerve compression, can also occur due to mass effect.44 Additional complications include exposure keratopathy due to hemangioma-induced exophthalmos12,44 and tear duct obstruction; the latter being relatively common, but does not result in visual loss. The exact incidence of these complications is unknown and may be changing with the advent of beta-blocker therapy (see discussion below). Several previous reviews have cited an incidence rate of 43-76% for amblyopia developing due to a periocular hemangioma.46 One group performed a population-based study of periocular hemangiomas over a 40-year period and reported a 19% rate of amblyopia, suggesting that the previously reported numbers were artificially elevated by referral bias.46 In our experience, it is far lower as long as treatment is instituted promptly.

Fig. 5 Mixed hemangioma with subtle deeper component with slight distortion of the eyelid margin. Although small in size, a deep component can exert pressure on the globe and induce astigmatism.

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Fig. 6 Mixed IH. Size N 1 cm, nasal location, and visual axis occlusion are features associated with worse visual outcome.

Although any hemangioma involving the orbit or eyelids can lead to ocular sequelae, those with segmental morphology and intraconal or extraconal involvement are most likely to be associated with ocular complications.37 Unfortunately, predicting intra/extraconal involvement on clinical exam alone is very difficult, with one study finding that no clinical feature could predict intra/extraconal involvement,37 and another reporting that globe deviation or mobility impairment were the only positive predictive clinical findings associated with intraorbital involvement.37,47 Other features associated with worse visual outcome include: upper eyelid location48; size greater than 1 cm, especially if associated with “nasal location, ptosis, lid margin change, proptosis, globe displacement, and strabismus”49; and evidence of occlusion.50 Occlusion of the pupil, in particular,

Fig. 7 Panels A, B, Segmental facial IH N 5 cm warrant further workup to evaluate for PHACE syndrome, including MRI/MRA of the head/neck, ophthalmologic exam, and echocardiogram. Any periorbital and/or intraorbital involvement requires close follow-up and treatment.

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Fig. 8 Indeterminate (partial segmental) superficial IH of the medial canthus. Partial ptosis and a deeper component (A and B) were worrisome features for impending visual impairment. Systemic beta-blocker therapy resulted in excellent improvement (C and D). By age 15 months (D) there was only minimal residual IH. Intermittent tear duct obstruction associated with this hemangioma (C) also resolved.

is associated with poor prognosis and should be treated as quickly and completely as possible.50,51 A sign of threatened occlusion was defined by one group as “upper or lower eyelid ptosis within 1 or 2 mm of the pupillary border”50 and signifies a patient who should be very closely followed with a low threshold for starting treatment (Figure 9). Additionally, even though a pupil may be unobstructed, if an upper or lower lid encroaches on binocular vision in certain gaze directions (eg, up or down gaze), it may lead to intermittent occlusion and amblyopia.52 Complete visual occlusion is a vision–threatening emergency, and these patients always deserve prompt and aggressive treatment.11 In addition to direct effects on the eye, segmental IH confer an additional risk of developmental and structural anomalies. PHACE syndrome, an acronym coined by Frieden et al in 199653 refers to the association of posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/aortic coarctation, and eye anomalies. Consensus criteria for major and minor associated eye findings are summarized in Table 2.54 The IH associated with PHACE syndrome are Table 1

Useful definitions

Term

Definition

Anisometropia

The two eyes have different refractive power, so that when the image is in focus in one eye, it is out of focus in the other Nearsighted Farsighted Eyes not properly aligned and look in different directions Vision from blurry eye is suppressed at the level of the visual cortex Inability to focus image on the retina due to a cylindrical component; when lines in one direction are in focus, perpendicular lines are out of focus Paralysis of ciliary muscles

Myopia Hyperopia Strabismus Amblyopia (aka “lazy eye”) Astigmatism

Cycloplegia

typically large (N 5 cm) and segmental.54 Affected infants with PHACE often have IH involving the periocular area and thus are at risk for both structural eye anomalies and the usual ocular morbidities such as anisometropia, astigmatism, visual axis obstruction, and strabismus; however, infants with PHACE without periocular hemangiomas can also have structural eye anomalies.5,54 All infants at-risk for PHACE syndrome (eg, facial IH N 5 cm diameter) should be seen by an ophthalmologist familiar with PHACE to evaluate for any associated ocular anomalies.54 Finally, potential complications may arise unrelated to the effect on vision. Ulceration, although a common complication of hemangiomas, especially segmental IH,53 is quite rare in the periocular region.55 A more frequent sequelae of IH in the periorbital area are permanent skin changes. These include residual fibrofatty tissue, anetoderma, and other skin alterations, which can distort anatomic landmarks, including the eyelid skin, lid margin, eyelashes, and eyebrows. Even without leaving overt scarring, hemangioma growth and involution may result in permanent eyebrow alopecia as well as distortion of the normal eyebrow anatomy, which can result in visible disfigurement of the central facial anatomy (Figure 10).56 See Table 3 for a summary of potential complications.

Approach to the exam: The dermatologist’s perspective Physical exam findings of the hemangioma will depend on the location within the skin, as well as within the orbit. Superficial hemangiomas appear brightly erythematous, whereas deep hemangiomas appear more violaceous or blue, often with few overlying telangiectasias. With palpation, hemangiomas that have palpable bulk are usually rubbery and somewhat compressible. Examination should include gentle eversion of the eyelids to evaluate for mucosal/conjunctival involvement. Examination should also include gross evaluation for pupil alignment, proptosis, as well as evaluation of eye movement, ensuring they are full and symmetric. The patient should be evaluated for excess tearing or unilateral accumulation of debris or crusting, as

Hemangiomas and the eye

Fig. 9 Lower eyelid hemangioma. This IH grew rapidly in the first 3 months of life and began to cause the lower lid to encroach on the visual axis, requiring initiation of systemic therapy. At age 6 years, there were minimal skin changes and no visual impairment.

these may be signs of tear duct obstruction. If there is concern for potential vision impairment due to hemangioma growth, the patient should be followed closely, every few weeks for the first few months given the known early growth characteristics of hemangiomas.30 Dermatologists caring for patients with IH should familiarize themselves with ophthalmology colleagues in their community who have either specialized pediatric training (eg, pediatric ophthalmology fellowship training) or familiarity with examination of infants. Pediatric training is essential in performing examinations in preverbal infants. The degree of experience among pediatric ophthalmologists seeing infants with IH is highly variable. A survey of members

Table 2

Ocular findings associated with PHACE syndrome

Retinal vascular abnormalities ⁎ Persistent fetal vasculature ⁎ Iris vessel hypertrophy “Morning-glory” disc ⁎ Peripapillary staphyloma ⁎ Optic nerve hypoplasia ⁎ Microphthalmia + Coloboma ⁎ + Congenital cataracts + Sclerocornea + Iris hypoplasia Exophthalmos Congenital third nerve palsy Horner syndrome Adapted from Pediatrics 2009;124:1447–56. ⁎ Major criteria, + Minor criteria.

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Fig. 10 Infantile hemangiomas involving the eyebrow may result in permanent eyebrow alopecia as well as distortion of the normal eyebrow anatomy. A, Deep, relatively large localized IH, also extending to the upper eyelid, should be referred for ophthalmologic evaluation. B, This hemangioma does not involve the eyelid or threaten vision; however, its sessile morphology is a high-risk feature for leaving permanent residual skin changes.

of the American Association of Pediatric Ophthalmology and Strabismus found that its members saw an average of 5.6 IH each year with some reporting seeing none, and others seeing as many as 50.57 The average number of hemangiomas seen over a physician’s career span was 48 with a range from 0 to 495.57 IH are notably heterogeneous in depth, size, and anatomic locations, and have unique growth characteristics. This makes their management potentially challenging even for experienced clinicians.58 The wide range of experience amongst pediatric ophthalmologists emphasizes the need to communicate with ophthalmology colleagues to ensure that they are aware of the specific concerns unique to IH, particularly in the growth phase, a time when infants with high-risk periocular IH need to be seen on a frequent basis. A note from an ophthalmologist, for example, Table 3

Potential complications

• Direct pressure inducing astigmatism or myopia (anisometropia) ⁎ • Ptosis with partial or complete occlusion of the visual field ⁎ • Strabismus due to mass effect or intramuscular involvement ⁎ (rare) • Optic nerve compression (rare) • Tear duct obstruction • Exposure keratopathy due to proptosis • Complications secondary to PHACE syndrome • Ulceration • Disfigurement ⁎ May result in amblyopia.

176 indicating “no glaucoma found, follow-up visit in 3 to 6 months,” would suggest confusion with port-wine stains and Sturge-Weber. A recommended follow-up visit in 6 to 12 months for a young infant with a growing periocular hemangioma would not be advisable and should prompt either further direct communications with the ophthalmologist to relay information about the natural history of IH or referral to another ophthalmologist for a second opinion. Additionally, referrals to an ophthalmologist should at a minimum include the suspected diagnosis of IH, level of certainty of the diagnosis, stage of growth or involution, and whether there is a concern regarding possible PHACE syndrome and associated structural anomalies. Specific questions such as “is astigmatism or amblyopia present?” and “if present, is it thought to be hemangioma-related?” can also be helpful.

Approach to the exam: The ophthalmologist’s perspective Pediatric eye exams should include evaluation of cycloplegic refractive error, visual acuity, as well as visual field testing. Visual field testing is only possible using confrontational techniques in young children. In preverbal children, visual acuity can be measured via several methods, including ‘preferential looking,’ and ‘visual evoked potential.’ A clinician who is experienced with these examinations is invaluable.59 The ophthalmologist can further assist dermatologists and other physicians caring for patients with hemangiomas by addressing several key issues: (1) are the ocular findings compatible with the diagnosis of infantile hemangioma (versus another diagnosis); (2) does the IH threaten vision by any mechanism (anisometropia, strabismus, occlusion, keratopathy, etc) and/or does the potential for visual threat exist; (3) are there ocular findings that suggest PHACE syndrome; (4) for patients receiving treatment, assessing

A.A. Spence-Shishido et al. response to treatment where ocular effects have been noted; and (5) in patients with ocular effects, is the threat to vision significant enough to require spectacles or patching, and if so, for how long. The ophthalmologist should continue to monitor the patient regularly, particularly at frequent intervals through the growth phase of the IH. Patients with amblyopia or visual compromise should be followed until visual maturity is achieved (around age 9), even after successful initial treatment of the hemangioma and/or amblyopia.9,12

Imaging Radiographic imaging is needed in some, but not all patients with periocular IH. Imaging may be needed to confirm the diagnosis in certain cases, for example, if the hemangioma presents only as a deep mass and/or with proptosis (Figure 11), globe deviation, or strabismus. If the presentation is atypical for IH (ie, fully formed lesion at birth, or appearance at later age), imaging should also be considered.60 Additionally, as there are only few clinical features that allow prediction of intraorbital/retrobulbar involvement,37 imaging can also assist with delineating the location and extent of the IH. Guidelines do not yet exist for routine imaging of periocular IH, but experts have suggested that globe displacement or eyelid thickening should prompt further imaging.60 Finally, as discussed earlier, large segmental facial hemangiomas also deserve imaging to evaluate for PHACE syndrome.60 There are several excellent reviews that describe the imaging features of infantile hemangiomas.12,61–63 Ultrasound images are helpful in delineating anatomic location and extent within the orbit though may be less helpful in evaluation of lesions in the posterior orbit, and results are operator-dependent.60,64,65 Ultrasound is an attractive option as it may be done relatively rapidly and does not require

Fig. 11 Retro-orbital hemangioma on right side presenting with rapid onset proptosis. A retro-orbital hyperintense mass with intraconal involvement is seen on T2-weighted MRI imaging.

Hemangiomas and the eye sedation, and as such, is also helpful for serial examinations.39 Further, the addition of color Doppler imaging to standard ultrasonography increases the ability to diagnose and distinguish between the varieties of orbital masses.65 Hemangiomas and rhabdomyosarcomas show intralesional blood flow on color Doppler.65 When malignancy is suspected, further imaging is indicated with an MRI with contrast or a CT scan. MRI with gadolinium contrast is the gold standard study to evaluate the hemangioma, confirm diagnosis, evaluate the extent of the IH/assess relationship to surrounding structures, as well as identify any associated anomalies.60,61

Differential diagnosis The characteristic appearance and growth characteristics (with early rapid proliferation and later slow involution) help to make the clinical diagnosis of infantile hemangioma; therefore, the diagnosis may be made, or refined, over the course of several clinic visits. The differential diagnosis of a periocular hemangioma includes other vascular tumors and malformations. In early superficial hemangiomas, especially before proliferation occurs, one should consider a capillary malformation, such as a port-wine stain or nevus simplex (salmon patch). Unlike a hemangioma, both of these are vascular malformations which are present at birth, neither of these proliferates; a nevus simplex will typically fade over time. Other vascular tumors and malformations to consider include the following: venous and/or lymphatic malformations, rapidly involuting congenital hemangioma, noninvoluting congenital hemangioma, tufted angioma, and kaposiform hemangioendothelioma. When lesions affect deeper areas of the orbit without any superficial component, it may be difficult to clinically confirm the diagnosis. In these instances, further imaging and biopsy may be warranted to evaluate for other concerning intra/periocular tumors, including rhabdomyosarcoma, neuroblastoma, and plexiform neurofibroma.44 In the pediatric population, rhabdomyosarcoma is the most common soft tissue malignancy in the periorbital area.66 These mesenchymal tumors often present rapidly, with proptosis and displacement of the globe.65,66 Alternatively, neuroblastoma is the most common metastatic tumor of the orbit, often with the primary tumor involving the abdomen.66 These tumors also present with proptosis and ptosis, but may also be associated with eyelid ecchymosis.39,66 Other orbital masses include developmental orbital cysts (including dermoid and epidermoid cysts, and teratomas).65,66 In children, dermoid and epidermoid cysts, also called choristomas, are the most common space-occupying mass in the orbit.65

Management Because IH resolve spontaneously, treatment is not needed in all patients; however, with periocular involvement,

177 active treatment should be considered in all cases. Treatment decisions depend on many factors, including location, size, findings on eye exam (proptosis, strabismus, globe displacement, lid margin change, visual axis obstruction), patient age, perceived growth potential, and parental preference. Figure 12 proposes an algorithm for management. If a patient is very young (b 4 weeks old) at the time of the initial visit, the potential for rapid growth remains. In these patients, thoughtful consideration of treatment options as well as close follow-up (eg, every 2 weeks) is recommended. In hemangiomas exhibiting rapid growth, concerning for threatening vision, or causing significant cosmetic disfigurement, active treatment is indicated. Complete occlusion of the visual axis is an ophthalmologic emergency and warrants immediate and aggressive therapy.11 Prevention of pupil occlusion is equally important given the poor visual prognosis associated with occlusion.50 Early treatment has been shown to improve outcomes. One study found that hemangioma-specific treatment initiated before 6 months of age improved anisometropic astigmatism with shrinkage of the hemangioma.50 Treatment should be selected and initiated in conjunction with an ophthalmologist who should continue to regularly monitor for response and assess further risk of amblyopia. Continued communication is crucial, as an ophthalmologist’s concern for threatened vision would warrant an alteration in treatment. Conversely, reassurance of a normal eye exam could help inform decisions about treatment and frequency of follow-up visits.

Medical management Beta-blockers The fortuitous discovery of the effectiveness of propranolol in IH has revolutionized management of patients with this disease including those with periocular disease.67 Currently, both topical beta-blockers, principally timolol, and oral beta-blockers, principally propranolol, are used in the management of periocular IH. A recently published systematic review of all literature published during the 4-year period after publication of the initial report by Leaute-Labreze et al found a response rate of 98% in IH treated with propranolol.68 Propranolol has also been demonstrated to improve outcomes specifically for periocular hemangiomas. One large systematic review examined 100 reported cases between 1 week and 18 months of age treated with oral propranolol for orbital and periocular hemangiomas.69 Propranolol was reportedly effective in 99% of cases (with clinical response noted as “improvement or resolution of the lesion”).69 “Blanching, softening, and early regression” were noted in the first 3 days of treatment, though “visible response” was reported to occur between 1 week and 6 weeks after starting propranolol.69 Although this review was unable to specifically look at improvement in visual function, several other groups have shown that propranolol therapy of periocular IH decreased associated astigmatism70–72 and anisometropia.70,71,73

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Fig. 12

Proposed algorithm for management periocular hemangiomas.

Propranolol therapy is reportedly more effective than oral corticosteroids (the previous “gold standard” systemic therapy), with a significantly lower incidence of adverse effects and a more rapid onset of response.74,75 Adverse effects of propranolol include sleep disturbance (most common), acrocyanosis, hypotension (though rarely symptomatic), gastrointestinal symptoms, respiratory symptoms, bradycardia (though rarely symptomatic), hypoglycemia, irritability, profuse sweating, rash, and temporary hypotonia. 68 Propranolol appears to be effective not only in the proliferative phase, but also after the growth phase is thought to be completed.71,76 Consensus guidelines for the initiation of propranolol have recently been published; representing literature review and expert opinion.77 These guidelines include recommendations for patient selection and monitoring, and are expected to be modified as more data become available. Knowledge is lacking regarding ideal treatment duration and taper schedule for periocular hemangiomas. Cessation of growth and rates of involution vary considerably with large size and deeper involvement being predictors of more prolonged growth phase and slower involution. Treatment duration needs to be tailored to fit the indication for treatment, risk of rebound growth, whether functional abnormalities of the eye are present, and how well the medication is being tolerated. In some cases treatments can be tapered relatively

quickly with cessation of treatment by 1 year of age or even younger, whereas in other cases, treatment is needed for a longer period of time. Particularly in cases where a systemic medication is being used, periodic eye examination to assess for improvement or worsening are very helpful in guiding the discontinuation or tapering of active therapy. Although many experts currently view propranolol as first-line treatment for those IH where systemic therapy is needed,74,75 not all agree.78 Of particular note, use of propranolol in PHACE syndrome requires further consideration because in the setting of coarctation or severe cerebrovascular disease, propranolol may be contraindicated. To date, there have been a number of published cases of patients with PHACE syndrome treated with propranolol without serious sequelae; however, a conservative approach is recommended with neurology and cardiology input when appropriate.79 Further experience and data from prospective, long-term studies are likely to continue to inform our management strategies and use of beta-blockers in infants with periocular hemangiomas. Topical beta-blockers After noting such remarkable success in the treatment of hemangiomas with systemic beta-blockers, several groups have further reported success with topical timolol for superficial hemangiomas.80–84 Topical timolol has been

Hemangiomas and the eye reported in one study to be successful in improving associated astigmatic anisometropia.85 In spite of this report, caution is advised when treating vision-threatening periocular hemangiomas, as one study found that timolol may be slower in achieving noticeable results, reporting “significant improvement” in their patients only after 12 to 16 weeks of therapy.86 In patients at high risk for, or already showing signs of, amblyopia, 12 to 16 weeks may be too long to wait. The side effect profile of topical timolol is thought to be favorable compared with the potential risks of systemic medications. To date, the only significant adverse event reported in the use of timolol for infantile hemangioma was sleep disturbance (reported in one out of 73 patients in a retrospective review).81 As this is a reported side effect of systemic beta-blockers, some systemic absorption of the topical timolol can be inferred. There is extensive ophthalmologic literature available on the use and safety of timolol eye drops for glaucoma in children and adults, and additional systemic effects have been reported.87 Systemic absorption of the medication applied to eye is thought to occur through the ocular and nasopharyngeal mucosa (through the nasolacrimal duct).87 Information regarding absorption of timolol via intact skin is lacking, but is likely less than absorption through mucosa.87 A recently published randomized control trial of timolol gel versus placebo applied to cutaneous hemangiomas, found no significant differences in the heart rate, systolic or diastolic blood pressure between treatment groups, suggesting minimal percutaneous absorption.86 At present, insufficient data exist regarding the efficacy of timolol for the use specifically in periocular hemangiomas. It can be argued, that if an infant presents to the dermatologist with a superficial periocular hemangioma, which is not obviously occluding the visual axis, and without evidence of proptosis or strabismus, a patient can be started on timolol treatment with plan for very close follow-up (ie, 2 weeks) to monitor for growth/progression. Because the ophthalmologic literature does suggest systemic absorption after intra-ocular administration, caution and close monitoring is suggested before use on mucosal surfaces (ie, conjunctiva). Corticosteroids For many years, corticosteroids—particularly intralesional and systemic—have been a mainstay of therapy for periocular hemangiomas. Intralesional injections have the advantage of localized targeting of hemangiomas, and have been shown to improve astigmatism88; but they are not without significant risk. Intralesional corticosteroid injections have been reported to cause localized eyelid necrosis,88,89 ophthalmic artery occlusion,90 central retinal artery occlusion,91 as well as systemic side effects such as adrenal suppression.92 In fact, one group suggested that intralesional corticosteroid should be contraindicated in the periocular area.93 It appears that these potentially catastrophic complications are rare; however, current data in the literature is insufficient to accurately estimate the incidence of these side effects.94,95 Intralesional corticosteroids continue to be used, and favored, by ophthalmologists,57 and one recent

179 study suggests that this treatment modality should remain in our armamentarium even after the advent of propranolol.96 Topical corticosteroids can be effective in the treatment of superficial hemangiomas, resulting in a decrease in size, but the effect on reducing astigmatism and anisometropia is less clear.95,97,98 Systemic corticosteroids have been shown to prevent the progression of proliferating hemangiomas, as well as improve visual function.99 They are associated with well-known systemic side effects, including adrenal suppression, immunosuppression, cushingoid appearance, hypertension, weight gain, irritability, and gastrointestinal upset.100 Several retrospective reviews have documented clinical superiority of propranolol over systemic corticosteroids with fewer reported side effects.74,75,101

Surgical management In very large and/or rapidly enlarging vision-threatening hemangiomas, especially those already resulting in anisometropia, astigmatism, strabismus, or visual axis occlusion, early surgical intervention has been proposed given the rapidity of improvement due to the relatively immediate shrinkage/removal of the hemangioma.102 Several reports emphasize early surgical intervention in those vision-threatening hemangiomas failing conservative/medical therapies,102,103 with many demonstrating significant improvement in identified amblyogenic features.102– 104 These studies recognize a window of opportunity, with one study suggesting surgery before 13 months, after which residual amblyopia caused by occlusion of the visual axis may be irreversible.103 Proponents of early surgical intervention note that advances in surgical instruments and products promoting hemostasis have allowed for the evolution of more refined and arguably safer surgical techniques58; however, periocular hemangiomas often intimately involve periocular structures, such as the arcus marginalis and extraocular muscles,58 so that complete removal may be difficult and recurrence may occur. Additionally, appropriate patient selection and preoperative imaging is key.104,105 Given the remarkable efficacy of systemic beta-blockers, particularly with the rapid visible shrinkage in IH, this treatment may supplant early surgical intervention unless clinical response to systemic treatment is deemed inadequate.106 Nonetheless, surgery remains an important treatment option in the hands of experienced surgeons. Laser The pulsed dye laser (PDL) has been used since the 1980s for the treatment of vascular lesions, but its role in the treatment of infantile hemangiomas is controversial.107 The use of PDL can cause serious and even permanent complications, including ulceration and scarring.108 The wavelength of PDL penetrates only 1.2 mm into the epidermis, limiting the usefulness of PDL to superficial hemangiomas exclusively.58 Laser therapy for periocular hemangiomas in infants can also be technically challenging, often requiring either the insertion of an eye shield into the eye of an awake, crying infant, or the

180 administration of general anesthesia. Proponents of laser therapy have demonstrated the safety and efficacy of the 595-nm PDL for superficial eyelid hemangiomas107; however, for many physicians, laser therapy in this location can be technically challenging. It is not an option that is universally available and/or easily accessible to all patients. With the advent of highly effective and well-tolerated systemic and topical beta-blocker treatments, in our opinion, laser surgery plays a minor role in the treatment of periocular hemangiomas. Management of amblyopia Management of visual impairment is usually done concomitantly with a pediatric ophthalmologist. Often, refractive errors (anisometropia) are corrected first, with the use of spectacles.59 Unique issues may arise in certain patients with periocular hemangioma: The IH may be too bulky to allow the spectacles to fit properly; additionally, spectacles may cause ulceration of the hemangioma due to constant friction.9 Occlusion therapy with patching or pharmacologic penalization with a cycloplegic eyedrops (ie, atropine) is subsequently used for residual amblyopia.59 It is important for dermatologists to be aware of these different therapies, and to encourage compliance with these adjunctive treatments. The dermatologist should continue to ensure close follow-up with the ophthalmologist to assure visual improvement, as well as to monitor for the rare phenomenon of reverse amblyopia (iatrogenic induction of amblyopia in the previously normal eye due to occlusion therapy).59,109 Patients with amblyopia should also be followed until visual maturity is achieved (around age 9).9,12

Conclusions Periocular IH are very heterogeneous, with varied morphologies and locations, both within the skin and within the orbit. They also display unique growth characteristics, including rapid early growth. Given the potential for complications, including vision loss, dermatologists, ophthalmologists, pediatricians, and other relevant specialists should have a working knowledge of IH and an approach to management. Open communication, and a multidisciplinary approach to the exam and management are in the best interest of patients with these potentially visionthreatening birthmarks.

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Hemangiomas and the eye.

Infantile hemangiomas are a common vascular birthmark with heterogeneous presentations and unique growth characteristics with early rapid growth and e...
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