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 with ≥ 1 hemangioma at any site,3 found that 12% had a

Infantile hemangiomas (IH) are a common birthmark
occurring in 4-5% of all infants, with female gender,
prematurity, Caucasian race, and multiple gestation preg-
nancies 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: FriedenI@derm.ucsf.edu (I.J. Frieden).
periocular IH (E. Baselga, MD, personal written
communication, October 2013). In contrast, a population-
based 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 commu-
nication, 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

http://dx.doi.org/10.1016/j.clindermatol.2014.10.009
0738-081X/© 2015 Elsevier Inc. All rights reserved.
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 diag-
nosis, 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 Numer-
ous 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 immunoreac-
tivity 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 prolifera-
tion 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 mac-
ules) followed by rapid proliferation, then slow involu-
tion.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 previ-
ously 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
172 A.A. Spence-Shishido et al.

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.

Periocular hemangiomas can further be classified by their

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.
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 hemangi-
omas 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 173

Fig. 6 Mixed IH. Size N 1 cm, nasal location, and visual axis
Fig. 4 Deep hemangioma involving the left orbit with associated occlusion are features associated with worse visual outcome.
ptosis but without overlying epidermal change. In addition to
evaluation by an ophthalmologist, radiologic imaging should be
considered to confirm diagnosis. Although any hemangioma involving the orbit or eyelids can
lead to ocular sequelae, those with segmental morphology
for useful ophthalmologic definitions). Amblyopia is caused and intraconal or extraconal involvement are most likely to
by abnormal/suppressed visual axis development (both eye be associated with ocular complications.37 Unfortunately,
and brain) due to abnormal images received from one eye, and predicting intra/extraconal involvement on clinical exam
is the most common preventable cause of monocular alone is very difficult, with one study finding that no clinical
childhood blindness in the United States.44 IH can result in feature could predict intra/extraconal involvement,37 and
amblyopia by three mechanisms: (1) direct pressure on the another reporting that globe deviation or mobility impair-
globe induces astigmatism or myopia causing an asymmetric ment were the only positive predictive clinical findings
refractive error between the two eyes (anisometropia)9,44; (2) associated with intraorbital involvement.37,47
partial or complete occlusion of the visual axis9,45; and (3) Other features associated with worse visual outcome
induction of strabismus (misalignment of the eyes) due to include: upper eyelid location48; size greater than 1 cm,
hemangioma mass effect or by involvement of the extraocular especially if associated with “nasal location, ptosis, lid margin
muscles.9 Of these, the first mechanism is far more common change, proptosis, globe displacement, and strabismus”49; and
than the others.9 Optic nerve compression, can also occur due evidence of occlusion.50 Occlusion of the pupil, in particular,
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. 7 Panels A, B, Segmental facial IH N 5 cm warrant further

workup to evaluate for PHACE syndrome, including MRI/MRA of
Fig. 5 Mixed hemangioma with subtle deeper component with the head/neck, ophthalmologic exam, and echocardiogram. Any
slight distortion of the eyelid margin. Although small in size, a deep periorbital and/or intraorbital involvement requires close follow-up
component can exert pressure on the globe and induce astigmatism. and treatment.
174
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
Myopia Nearsighted
Hyperopia Farsighted
Strabismus Eyes not properly aligned and
look in different directions
Amblyopia Vision from blurry eye is suppressed at
(aka “lazy eye”) the level of the visual cortex
Astigmatism 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
Cycloplegia Paralysis of ciliary muscles
A.A. Spence-Shishido et al.
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 alter-
ations, 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 175

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 Fig. 10 Infantile hemangiomas involving the eyebrow may result
the visual axis, requiring initiation of systemic therapy. At age 6 in permanent eyebrow alopecia as well as distortion of the normal
years, there were minimal skin changes and no visual impairment. 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
these may be signs of tear duct obstruction. If there is concern permanent residual skin changes.
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 the American Association of Pediatric Ophthalmology and
of hemangiomas.30 Strabismus found that its members saw an average of 5.6 IH
Dermatologists caring for patients with IH should each year with some reporting seeing none, and others seeing
familiarize themselves with ophthalmology colleagues in as many as 50.57 The average number of hemangiomas seen
their community who have either specialized pediatric over a physician’s career span was 48 with a range from 0 to
training (eg, pediatric ophthalmology fellowship training) 495.57 IH are notably heterogeneous in depth, size, and
or familiarity with examination of infants. Pediatric training anatomic locations, and have unique growth characteristics.
is essential in performing examinations in preverbal infants. This makes their management potentially challenging even for
The degree of experience among pediatric ophthalmologists experienced clinicians.58
seeing infants with IH is highly variable. A survey of members The wide range of experience amongst pediatric ophthal-
mologists emphasizes the need to communicate with ophthal-
mology colleagues to ensure that they are aware of the specific
Table 2 Ocular findings associated with PHACE syndrome concerns unique to IH, particularly in the growth phase, a time
Retinal vascular abnormalities ⁎ when infants with high-risk periocular IH need to be seen on a
Persistent fetal vasculature ⁎ frequent basis. A note from an ophthalmologist, for example,
Iris vessel hypertrophy
“Morning-glory” disc ⁎
Table 3 Potential complications
Peripapillary staphyloma ⁎
Optic nerve hypoplasia ⁎ • Direct pressure inducing astigmatism or
Microphthalmia + myopia (anisometropia) ⁎
Coloboma ⁎ + • Ptosis with partial or complete occlusion of the visual field ⁎
Congenital cataracts + • Strabismus due to mass effect or intramuscular
Sclerocornea + involvement ⁎ (rare)
Iris hypoplasia • Optic nerve compression (rare)
Exophthalmos • Tear duct obstruction
Congenital third nerve palsy • Exposure keratopathy due to proptosis
Horner syndrome • Complications secondary to PHACE syndrome
Adapted from Pediatrics 2009;124:1447–56. • Ulceration
⁎ Major criteria, • Disfigurement
+
Minor criteria. ⁎ 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 astigma-
tism 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 cyclople-
gic 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
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.
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 segmen-
tal 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
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 distin-
guish 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 heman-
gioma, 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 rhabdomyo-
sarcoma, 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 displace-
ment, 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, reassur-
ance 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 propran-
olol 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
178
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 symp-
tomatic), 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 recommen-
dations 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
A.A. Spence-Shishido et al.
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 consider-
ation 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 perio-
cular 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 ophthal-
mologic 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 random-
ized 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 occlu-
sion,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 contraindi-
cated 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, immuno-
suppression, 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 anisometro-
pia, 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 selec-
tion 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 concom-
itantly 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 morphol-
ogies 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 vision-
threatening birthmarks.
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