Infantile Hemangioma: Treatment with Surgery or Steroids Louise A. Mawn, M.D.

ABSTRACT Background and Purpose: Infantile hemangiomas (IH) often pose a significant risk to visual development. The lesions interfere with visual development by causing deprivation, astigmatism, or strabismus. Propranolol has been suggested as the new standard of care for treatment of IH. Alternative treatments such as intralesional steroids or surgery may need to be considered as equal or better treatments in some cases. The purpose of this study was to evaluate the potential risks and benefits of the various modalities for periocular IH. Method: A literature search was conducted for IH and propranolol, steroids, and surgery. The pertinent published literature on surgical resection of IH were reviewed and summarized. A retrospective analysis was also performed of the Vanderbilt Children’s Hospital (VCH) surgical case series of twelve children who underwent surgical resection of a sight threatening IH. Results: Seven articles reported twenty or more patients treated with propranolol for IH. Many of these patients only had a partial response to propranolol in spite of months of treatment. In addition to the impact on IH, propranolol has been demonstrated to block neural pathways critical for learning and memory. Twelve children underwent surgical resection of a visual threatening IH at VCH. Two of these children had failed treatment with oral propranolol. The average time of surgery was 80 minutes. All twelve children had immediate resolution of the visual compromise. Conclusion: Early surgical intervention can successfully and quickly result in excellent visual and anatomic outcomes. Propranolol may have unrecognized neurocognitive impact and should be reserved for those lesions unamenable to surgical or local steroid injection.

INTRODUCTION Infantile hemangiomas are the most common orbital tumor of infancy.1 Infantile hemangiomas are not present at birth,

but typically become apparent by 2 months of age. These tumors can be either localized or segmental.2 The segmental lesions cover a large facial area and are at higher risk for associated systemic complications.

From the Vanderbilt Eye Institute, Nashville, Tennessee. Requests for reprints should be addressed to: Louise Mawn, M.D., Vanderbilt Eye Institute, 2311 Pierce Avenue, Nashville, TN 37232-8808; e-mail: [email protected] Presented as part of a Symposium of the Joint Meeting of the American Orthoptic Council, the American Association of Certified Orthoptists, and the American Academy of Ophthalmology, Chicago, Illinois, November 11, 2012. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York, to the Vanderbilt Eye Institute and Physician Scientist Award. © 2013 Board of Regents of the University of Wisconsin System, American Orthoptic Journal, Volume 63, 2013, ISSN 0065-955X, E-ISSN 1553-4448

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With both localized and segmental hemangiomas, ophthalmic complications can occur. Amblyopia is the term for failure of normal vision to develop in an otherwise normal eye. Amblyopia caused by infantile hemangiomas can lead to permanent visual impairment.3 Hemangiomas can cause all three forms of amblyopia, deprivation, astigmatic and strabismic disruption of visual neural circuitry. Even though nearly 70% of hemangiomas will involute and resolve over the first 7 years of life, the lack of visual development will be permanently established.4 The critical period for the development of binocular visual development is 3-24 months.5 Obstruction of the visual axis leads to dense amblyopia. The earlier and longer the obstruction the more difficult treatment can be to develop vision in the eye. If the critical time period of the first months of life has already elapsed, opening the visual axis may not allow for vision to develop. Reversal of an astigmatic deficit after age 3-5 years may not correct a binocular visual abnormality.5 Successful treatment schedules for amblyopia intervention are well established. A lesion blocking vision must be addressed early in the first year of life. In spite of the wellestablished amblyopia protocols, the treatment of periorbital infantile hemangiomas is controversial. For those lesions interfering with visual development, some form of treatment must be considered. Propranolol, a nonselective beta blocker approved for cardiovascular disease, was first proposed as an effective treatment for infantile hemangiomas in 2008 by LéautéLabrèze and colleagues.6 These French dermatologists made a serendipitous observation of rapid resolution of segmental hemangiomas in two children treated with propropranolol for heart disease. The investigators went on to treat nine additional children and then reported their exciting findings. Propranolol is a nonselective beta an-

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drenergic receptor blocking medication approved for the treatment of hypertension, heart disease, migraine, and essential tremor. It competes with beta-adrenergic receptor stimulating agents for receptor sites. Propranolol is contraindicated in cardiogenic shock, sinus bradycardia, asthma, and in hypersensitivity to propranolol. The safety and effectiveness of propranolol in pediatric patients has not been established. Propranolol for treatment of periocular hemangiomas represents an off label use of the medication. Widespread use of the medication in otherwise healthy infants with both segmental and localized hemangiomas was quickly adopted following the letter to the New England Journal of Medicine. Beta blockers have shown promising effects when used both systemically and topically for the treatment of infantile hemangiomas.6-11 Some periocular hemangiomas fail to respond to propranolol and others recur after propranolol is stopped.12-16 Propranolol does not lead to resolution of all infantile hemangiomas, can require months of treatment to decrease the size of an orbital lesion, and the off-label use was adopted without extensive study of the possible deleterious effects in otherwise healthy infants. Caution regarding this off-label use has been urged by some authors.10, 17 Case series over the last 20 years have documented that surgical resection of infantile hemangiomas is successful in reversing deprivational, strabismic, and even astigmatic amblyopia if performed early.18-20 In addition, these previous reports have shown that surgical resection is associated with few to no complications.4, 21-24 Local and systemic corticosteroid treatments are the alternative well-established medical treatments with known side effects in infants with hemangiomas. The objective of this study was to consider the treatment rationale for infantile hemangiomas with a specific evaluation of the potential risks and benefits of a re-

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cently proposed new standard of care: beta blocker versus more traditional treatment with surgery or steroids. METHODS A systematic literature review (using PubMed®) of English language publications was conducted through November 6, 2012. We employed a multi-term search query to find articles that met the following inclusion criteria: 1) were original reports of infantile hemangioma cases; 2) involved medical or surgical treatment; or 3) were articles addressing propranolol side effects. The articles were reviewed for both the efficacy and untoward effects of propranolol, surgery, and steroids. We elected to exclude those propranolol case series of less than twenty patients. In addition to the literature review, all Vanderbilt Children’s Hospital patients were reviewed who were less than age 18 years identified by a search of the electronic billing system for an international classification of disease 9th edition (ICD-9) diagnosis code of 228.00-228.1 (hemangioma) and who also underwent surgical treatment. We retrospectively studied the charts of twelve patients with infantile hemangiomas treated surgically between 2000 and 2012. Vanderbilt University Institutional Review Board Approval was obtained and conformed to the requirements of the United States Health Insurance Portability and Privacy Act. The data examined was history including age of presentation, visual status, treatment, procedure, size of specimen, and outcome. RESULTS Seven case series reporting propranolol treatment of periocular hemangiomas with greater than twenty patients were found.25-31 Infantile hemangiomas required approximately 6 months treatment with propranolol (Table 1). Nearly all of the

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seven studies reported that many children only had partial response to the propranolol. In one study, in which the extent of resolution of the hemangioma was graded, only 8/55 hemangiomas showed complete regression with propranolol treatment.29 The authors speculated that the relatively older age (mean 6.4 months; range 1.2-35.5 months) of their patients may have been the reason that so few completely responded to propranolol. The available studies only report on adverse effects on infants while undergoing treatment with propranolol. The reported side effects during propranolol treatment of IH in the case series reviewed and other reports included bradycardia, hypotension, hypoglycemia, wheezing, insomnia, agitation, and nightmares (Table 1).32-36 Studies evaluating the long-term adverse effect of propranolol treatment for infantile hemangioma were not discovered, but literature describing propranolol’s ability to block the betanoradrenergic receptors active in learning was found during the literature review.37, 38 Propranolol treatment was frequently described in the seven propranolol case studies as superior to the previous mainstay of medical treatment, intralesional or system steroids.25, 27-31 However, there have been reports of both propranolol and intralesional and systemic steroids showing only a partial response, and additionally some infants responded to steroids after failing propranolol.15, 31, 39 Janmohamed et al. reported a cohort of thirty-four patients treated with intralesional steroids for pericoular hemangiomas.40 There were no complications. Ninety-one percent of the children treated with the local steroid injection showed regression of the IH at 12 months. The authors also highlighted that propranolol is contra-indicated in children with asthma, PHACE syndrome, and some cardiac diseases.40 In contrast to the time lag between medical treatments and surgical treatment, the resolution of the visual deprivation

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TABLE 1 CASE SERIES OF INFANTILE HEMANGIOMAS TREATED WITH PROPRANOLOL

Author

Year

Months of Treatment

Number of Patients

Georgountzou25 Balma-Mena26

2012 2012

7.6 (SD 3.1) 7.3 (SD 3.8)

24 44

Talaat27

2012

6.55 (SD 0.75)

50

Lv28

2012

3.54 (SD 1.1)

37

Schupp29

2012

6

55

Snir30

2011

7.3

30

Buckmiller31

2010

5.5

41

or compromise is immediately realized with surgery. Nine case series reporting surgical resection of periocular hemangiomas were found during the literature review.4, 18-24, 41 Only one of these surgical series reported greater than twenty patients.20 None of these case series had any major complications or required critical care admission. Ninety-two percent of the surgical patients reported had resolution of amblyopia following surgery.4, 18, 22-24 A review of the twelve children operated on at VCH mirrored the results in the literature for surgical treatment of infantile hemangiomas (Table 2). The majority of the patients were female (92%). The average age of the twelve children was 10.2 months (SD 12.11). The average operative time was 80 minutes (SD 40) and the mean size of the surgical specimen was 2 cm (SD 0.81). All of the VCH patients had successful treatment of the

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Complications (# Patients)

Failure or Recurrence

Hypotension (4) Hypotension, shortness of breath, mood changes, gastrointestinal symptoms, cold extremities (14) NR

Regrowth (3) Regrowth (6/16 after discontinued)

Diarrhea (9), nausea (1), restless sleep (1) Cold extremities (6), exanthema/dry skin (3), fatigue (4), gastrointestinal (2), bronchitis/asthma (2) Wheezing, loss of appetite, diarrhea, vomiting 11/26 Somnolence (6), gastroesophageal reflux (2), rash (1), respiratory syncytial virus exacerbation (1)

Partial regression 15/50, regrowth (2) Partial regression 11/37 Partial regression (46/55), no response (1), surgery (2)

52.5% improvement in involved area Partial regression (15), surgical excision (3), No response (1)

amblyopia. Two of the 12 children, one 6 months old and the other 18 months old, were referred by pediatric ophthalmology after failure to adequately respond to propranolol. Both propranolol failures had amblyopia from an obstructive lesion (Figures 1 and 2). The 6-month-old sent for surgical consideration had mechanical ptosis from a lid margin lesion, treated since age 2 months with some response to the propranolol. The 18-month-old had 4 D of astigmatism. In addition to propranolol, she had also been treated with topical timolol to the lesion, glasses and patching of the left eye 2 hours per day. The propranolol had been started at age 4 months and stopped at age 9 months because of failure to respond to the medication. Both children with amblyopia and hemangiomas nonresponsive to propranolol had equal vision following resection of the hemangioma (Figures 1 and 2).

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TABLE 2 VANDERBILT CHILDREN’S HOSPITAL INFANTILE HEMANGIOMA SURGICAL PATIENTS Case

Age (months)

Sex

Size Lesion (cm)

Surgery (min.)

1 2 3 4 5 6 7 8 9 10 11 12 Average

6 3 36 2 33 2 4 4 3 6 18 6 10.25 (12.11)

F F M F F F F F F F F F F (92%)

1.5 1.5 3 1 2 3.4 3 1.5 2.2 1 2.4 1.5 2.0 (0.81)

52 45 180 115 100 76 67 49 104 43 61 63 79.58 (39.74)

DISCUSSION The primary risk of periocular hemangiomas is visual loss from amblyopia.1, 42, 43 All treatment options for periocular hemangiomas involve some risk and vary in efficacy and time course to impact on the lesion. Obstruction of the visual axis or amblyopia related to an upper lid lesion was the most common reason for ophthalmic plastic treatment in our series. This finding may represent a selection bias of a surgical practice. Surgery typically has an immediate impact on mechanical ptosis or visual obstruction. A systematic review of the literature showed some evidence that treatment with both propranolol and steroids improves the visual outcome in children with infantile hemangiomas.30, 44 However, it is equally apparent from the literature that medical treatment can take months to achieve even a partial regression of a periocular hemangioma.5, 30 There are periocular hemangiomas that pose a significant threat to visual development. For these high-risk lesions, surgery may prove the most timely, effective, efficient, and safe modality to achieve vision development. Our findings are consistent with other

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FIGURE 1: Early surgical resection of amblyogenic localized infantile hemangioma. Six-month-old girl sent for evaluation of amblyogenic left upper eyelid mass. She had been treated with propranolol for 4 months for deprivational amblyopia. Preoperative photo (top) and 1 week postoperative photograph with visual axis cleared (bottom). (Photos courtesy of author.)

case series of surgical management of infantile hemangiomas.4, 18-24, 41 Withholding the option of surgical excision of a potentially devastating tumor, is inappropriate. The advantages of surgical excision

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FIGURE 2: Early surgical resection of infantile hemangioma occluding visual axis. Eighteen-month-old girl treated from age 4 to 9 months with propranolol, then topical timolol, patching, and glasses for deprivational and astigmatic amblyopia (top). The 4 D astigmatism cleared following resection. At age 27 months, she had equal vision in both eyes with absence of any residual component (bottom). (Photos courtesy of author.)

beta-adrenergic receptors blocked by propranolol are specifically required to induce long-term memories and to learn.37 Not only are the long-term neurocognitive effects of propranolol use in infants poorly understood, but propranolol does not always change the growth of an infantile hemangioma (Figures 1 and 2).12-14 With more time and experience, information on long-term effects of propranolol on periorbital hemangiomas will be available to guide treatment decisions. The available information is not sufficient to provide adequate evidence supporting propranolol as the only, first-line, or best treatment for all periocular hemangiomas Ophthalmologists play a pivotal role in assessing the risks and benefits of each of the possible treatment modalities for vision-threatening infantile hemangiomas. Ideally, these children can best be managed with a multidisciplinary vascular tumor board, in which a comprehensive panel of complimentary experts can advise as to the pros and cons of each treatment option for the individual child. REFERENCES

include immediate resolution of deprivation amblyopia and disfigurement, as well as prevention of local recurrence. Surgical excision should be utilized in cases where periorbital infantile hemangiomas are causing visual obstruction, induced astigmatism, or deformity. Surgical intervention may provide the most effective and safest option of treating some infantile hemangiomas. The impact from months of treatment with a beta blocker in early childhood in an otherwise healthy child is unknown. Propranolol acts as a neuromodulator and prevents noradrenaline from binding to its receptors in the amygdala and in the hippocampus.38 This area of the brain is active in processing emotional experiences and in the creation of memory. The very

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36. de Graaf M, Breur JM, Raphael MF, Vos M, Breugem CC, Pasmans SG: Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants. J Am Acad Dermatol 2011; 65:320-327. 37. Mihov Y, Mayer S, Musshoff F, Maier W, Kendrick KM, Hurlemann R: Facilitation of learning by social-emotional feedback in humans is betanoradrenergic- dependent. Neuropsychologia 2010; 48:3168-3172. 38. Hurlemann R, Walter H, Rehme AK, Kukolja J, Santoro SC, Schmidt C: Human amygdala reactivity is diminished by the beta-noradrenergic antagonist propranolol. Psychol Med 2010; 40:1839-1848. 39. Rossler J, Schill T, Bahr A, Truckenmuller W, Noellke P, Niemeyer CM: Propranolol for proliferating infantile haemangioma is superior to corticosteroid therapy: A retrospective, single centre study. J Eur Acad Dermatol Venereol 2012; 26:1173-1175. 40. Janmohamed SR, Madern GC, Nieuwenhuis K, de Laat PC, Oranje AP: Evaluation of intralesional corticosteroids in the treatment of peri-

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Key words: infantile hemangioma, amblyopia, propanolol, surgery, steroids, periocular

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Infantile hemangioma: treatment with surgery or steroids.

Infantile hemangiomas (IH) often pose a significant risk to visual development. The lesions interfere with visual development by causing deprivation, ...
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