Original Article - World Health Organizationapplications.emro.who.int/imemrf/Middle_East_Afr_J...298...

298 Middle East African Journal of Ophthalmology, Volume 18, Number 4, October - December 2011

Original Article

INTRODUCTION

Infantile hemangioma (IH) is a common benign orbital tumor that occurs more frequently in females (female to

male ratio 3:1). IH occurs more frequently in premature infants and in the products of multiple gestation. Prenatal associations include older maternal age, placenta previa, and pre-eclampsia.1 The natural history of the tumor includes a proliferative phase that may last the full first year of life, followed by an involution phase that is completed between 5 years and 8 years of age. The maximum growth occurs during the first 4–6 months of life. Generally, between 1 year and 5 years of age,

IH remains quiescent or it may begin to involute.2,3 Although most hemangiomas are benign and require no intervention, an IH can cause complications due to the location of the lesion and the association with systemic anomalies. Intervention is warranted for large disfiguring lesions or lesions that impair vital functions [Table 1].4

Various options are available for the treatment of IH.5,6

Corticosteroids have been used as the first-line therapy since their discovery in the 1960s. Corticosteroid therapy for IH can result in a varied response, with some authors reporting remarkable improvement in 30%-55% of cases and others

Departments of Ophthalmology, 1Dermatology, 2Cardiology, 3Medical Imaging and 4Child Health, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman

Corresponding Author: Dr. Abdullah Al-Mujaini, Department of Ophthalmology, Sultan Qaboos University Hospital, Sultanate of Oman. E-mail: [email protected]

ABSTRACT

Purpose: To investigate the efficacy and safety of oral propranolol in the management of periorbital infantile hemangioma in four subjects.Materials and Methods: Consecutive patients who presented with periorbital capillary hemangioma with vision-threatening lesions were prospectively enrolled in this study between January 2009 and October 2010. All subjects underwent treatment with 2 mg/kg/day oral propranolol. All subjects underwent ocular, systemic, and radiologic evaluations before treatment and at periodic intervals after starting therapy. Side effects from therapy were also evaluated. Results: Four subjects, between 3 months and 19 months of age, with periorbital hemangioma were enrolled in this study. Two subjects had been previously treated with oral corticosteroids with unsatisfactory response. All subjects had severe ptosis, with the potential for deprivation amblyopia. Three subjects had orbital involvement. After hospital admission, oral propranolol was initiated in all subjects under monitoring by a pediatric cardiologist. Subsequent therapy was performed with periodic out-patient monitoring. All subjects had excellent response to treatment, with regression of periorbital and orbital hemangioma. There were no side effects from therapy. Conclusions: Oral propranolol for periorbital hemangioma was effective in all the four subjects. Oral propranolol may be appropriate for patients who are nonresponsive to intralesional or systemic steroids. In patients with significant orbital involvement and lesions causing vision-threatening complications, oral propranolol can be the primary therapy.

Key words: Amblyopia, Infants, Orbital Hemangioma, Propranolol

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DOI: 10.4103/0974-9233.90131

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Oral Propranolol for the Treatment of Periorbital Infantile Hemangioma: A Preliminary Report from Oman

Beena Harikrishna, Anuradha Ganesh, Sana Al-Zuahibi, Samia Al-Jabri, Ahmed Al-Waily1, Adil Al-Riyami2, Faisal Al-Azri3, Feraz Masoud4, Abdullah Al-Mujaini

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Middle East African Journal of Ophthalmology, Volume 18, Number 4, October - December 2011 299

reporting unchanged status in 40% of cases and continued proliferation in the remaining cases.7 Therapy is most effective when initiated during the proliferative phase. Oral prednisolone (2–3 mg/kg/day) over a period of 6 months is a commonly used therapy. However, systemic steroids are associated with side effects including gastrointestinal upset, weight gain, growth retardation, hypertension, adrenal suppression and, rarely, immunosuppression. Intralesional corticosteroid injection was introduced to circumvent the adverse systemic side effects.8 However, intralesional corticosteroids carry the risks of skin hypopigmentation, fat atrophy, lid necrosis, and central retinal artery occlusion.9

Propranolol, a nonselective beta-blocker, is a promising treatment modality for IH and has been shown to be effective and safe.10 In the current study, we prospectively studied the efficacy and safety of oral propranolol in four children with proliferating and complicated infantile hemangiomas.

MATERIALS AND METHODS

Consecutive patients with periorbital capillary hemangioma, with vision threatening lesions, who presented to our institution between January 2009 to October 2010 were treated with oral propranolol and followed up prospectively. Prior to commencing

treatment, a comprehensive ophthalmic examination was performed, which included assessment of ptosis and globe position, measurement of visual acuity with age-appropriate methods (quality of fixation response in infants), orthoptic assessment, anterior segment evaluation with slit lamp, dilated fundus examination, and cycloplegic refraction. Data were collected on the extent of periorbital hemangioma and complications such as ptosis, proptosis, strabismus, astigmatism, and amblyopia. Magnetic resonance imaging (MRI) of the orbits was performed to establish the diagnosis and determine the extent of orbital involvement. All subjects underwent a pediatric evaluation to exclude systemic anomalies, neuroimaging to rule out intracranial abnormalities, and abdominal ultrasonography to assess visceral involvement. All subjects underwent a complete systemic examination to establish cardiovascular and respiratory fitness, chest x-ray, electrocardiography (EKG), and echocardiography (echo).

Oral propranolol at a dose of 1 mg/kg/day in three divided doses was administered to all subjects. Propranolol syrup was prepared from tablets. While initiating therapy, all children were admitted in order to monitor pulse rate and blood pressure every half an hour for the first 4 hours. If the child tolerated the treatment well, therapy was continued on an out-patient basis and the subjects (subjects’ caregivers/parents) were requested to return 1 week after discharge. The dose was increased to 2 mg/kg/day in three divided doses if there were no adverse effects from the initial therapy. The subjects were admitted for cardiac monitoring as described above. The subjects were maintained on oral propranolol thereafter and followed up at monthly intervals. Data were collected at each follow-up visit on the response to treatment (extent and color of the lesions) and the level of ptosis, proptosis, and amblyopia. Additionally, screening for cardiovascular and metabolic side effects of propranolol was performed at each visit by a cardiologist.

This study was approved by the Research Ethics Committee of the College of Medicine at Sultan Qaboos University, Oman. Written informed consent was obtained from the parents of all subjects.

RESULTS

Four subjects (three females; one male) between 3 months and 19 months of age met the inclusion criteria. The patient characteristics are summarized in Table 2.

Two subjects had passed the proliferative phase and were older than 1 year of age when therapy was initiated. These subjects had undergone treatment with high-dose prednisone for several months with a poor response and had rebound growth of the hemangioma after steroid withdrawal. One child developed a cushingoid appearance due to the therapy.

Table 1: Local and systemic complications of hemangioma with associated anomaliesComplications of hemangioma

Local Complications Ulceration, Hemorrhage, Infection, Necrosis

According to Location / Morphology

Periorbital and retrobulbar Ocular axis occlusion, astigmatism, amblyopia, optic nerve compression

Ear Obstruction of external auditory canal - otitis externa, hearing loss

Nasal tip, ear and large facial hemangioma

Permanent scarring, disfigurement

Segmental "beard area," central neck

Airway hemangioma - life-threatening complications

Subglottic Stridor, respiratory failurePerioral Ulceration, disfigurement, feeding

difficultiesPerineal, axilla and neck UlcerationMultiple hemangiomas Visceral involvement (especially

liver, gastrointestinal tract)Large Hemangiomas High-output cardiac failure

Associated anomaliesPHACES syndrome (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, sternal clefting)PELVIS syndrome (perineal hemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus, and skin problems)SACRAL syndrome (spinal dysraphism, anogenital anomalies, cutaneous anomalies, and renal and urologic anomalies associated with angioma of lumbosacral region)

Harikrishna, et al.: Hemangioma and Oral Propranolol




All subjects had vision-threatening lesions due to ptosis (n=4), astigmatism (n=4), proptosis (n=1), and strabismus (n=1). Deep amblyopia was evident in two subjects. MRI brain and orbit showed deep extension of orbital hemangioma in one subject. Two subjects had orbital involvement. There were no features suggestive of the posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, sternal clefting (PHACES) syndromein any subject. None of the subjects had visceral lesions on abdominal ultrasonography. Systemic workup revealed no contraindications for systemic beta-blocker therapy in any of the subjects.

Subject 1 was a 19-month-old female who presented with an extensive hemangioma involving the right periorbital region, right cheek, tip of the nose, and upper lip. She had severe ptosis, proptosis, esotropia, myopic astigmatism, and deep amblyopia of the right eye [Figure 1a]. Hypertrophy of underlying tissues, ulceration, and severe disfigurement was noted. MRI showed deep intraorbital extension. She was treated with several injections of intralesional triamcinolone at multiple sites and with oral predisolone twice during the first year of life; however, she had ill-sustained regression and rebound growth of the tumor after steroid cessation. We initiated oral propranolol and, at the time of writing, she has continued therapy for over 12 months [Figure 1b].

Subject 2 was a 12-month-old female who presented with extensive hemangioma of the right periorbital region and forehead, left parotid region, ear and lower lip, airways, right upper limb, and upper chest [Figure 2a]. She had moderate to severe ptosis, myopic astigmatism, and amblyopia. Significant tissue distortion by both the superficial and deep components of the hemangioma, ulceration, and severe disfigurement were

noted. She had twice received a course of pulse steroids, with transient improvement of the hemangioma. Oral propranolol was initiated and, at the time of writing, she has continued therapy for 10 months [Figure 2b].

Subject 3 was a four-month-old male, ex-preterm, born at 35 weeks of gestation, who presented with a left upper lid subcutaneous hemangioma, causing complete ptosis and astigmatism [Figure 3a]. He had another small lesion in the chest on the same side. Propranolol was started shortly after presentation. A visible shrinkage of the hemangioma was noted within 24 hours of commencement of therapy. He has continued propranolol for 5 months at the time of writing [Figure 3b].

Subject 4 was a 3-month-old girl who presented with a right upper lid hemangioma that caused complete ptosis, exotropia, and astigmatism of the right eye, with exfoliation of the periorbital skin [Figure 4a]. She had extraconal extension of hemangioma into the right orbit. Oral propranolol therapy was commenced and an accelerated involution of the hemangioma was observed. She has continued propranolol for 3 months at the time of writing [Figure 4b].

All subjects remained systemically stable at the initiation of treatment and during follow-up. Although all subjects showed visible signs of tumor regression, an accelerated involution of the hemangioma was observed in the subjects who were below 6 months of age at the time of initiation of therapy. Notable regression in the deeper orbital components was observed on examination and imaging in all subjects [Figure 5]. No adverse effects were noted. All subjects underwent occlusion therapy for amblyopia and correction of refractive error over the same period. All subjects had remarkable improvement in vision.

Two subjects required concomitant therapy with intralesional steroids for poorly regressing lip lesions. All subjects were maintained on propranolol at a dose of 2 mg/kg/day at the time of writing (average duration 6 months). We plan to gradually stop therapy over 3 months, when no more regression is observable (both clinically and by imaging).

DISCUSSION

Although IH is usually innocuous, with spontaneous involution occurring in the first five years of life, 10%–20% of infants with IH require intervention during the proliferative phase to prevent or reduce complications, which include disfigurement, interference with breathing, life-threatening pressure over the internal organs, and local complications such as hemorrhage, ulceration, and necrosis.11 Periorbital lesions pose a risk to vision through occlusion of the pupil, compression of the globe, and expansion in the retrobulbar space, leading to amblyopia, strabismus, astigmatism, and optic nerve atrophy.12,13

Table 2: Demographic data and clinical manifestations of study subjects

Subject Age at initiation of treatment with propranolol

Sex Hemangioma Side Previous treatment

1 19 months F Extensive facial hemangioma with intraorbital extension

Right Systemic and intralesional steroids

2 12 months F Extensive hemangioma of face, airways, upper limb, and chest

Both sides

Systemic steroids

3 4 months M Upper lid and small lesion on chest

Left nil

4 3 months F Upper lid with extraconal orbital involvement

Right nil





Direct intervention such as local corticosteroid injection, laser therapy, and surgical excision are not suitable for IH with deep orbital components due to poor access and risk of injury to the optic nerve and extraocular muscles.5 Conventional pharmacological treatment with systemic corticosteroids may be efficacious within 2–3 weeks of initiating treatment, but can cause significant systemic effects such as cushingoid facies, stunted growth, gastrointestinal symptoms, hypertension, and hypertrophic obstructive cardiomyopathy.14 In the treatment of hemangiomas steroids likely have multiple modes of action, including an anti-anabolic effect, a vasoconstrictive effect, possible pharmacologic inhibition of angiogenesis, and inhibition of fibrinolysis activators in the vessel walls; all of these can increase the effect of propranolo.15

Other agents are less predictable and have more serious side

Figure 1: Subject 1 - a) Pretreatment; b) after 8 months of treatment with oral propranolol for infantile hemangioma

a bFigure 2: Subject 2 - a) Pretreatment; b) after 9 months of treatment with oral propranolol for infantile hemangioma

a b


a b

Figure 5: Magnetic resonance imaging of the orbit and brain of subject 2 - coronal T1-W fat-suppressed postcontrast enhancement images; a) Pretreatment; b) after 9 months of treatment with oral propranolol for infantile hemangioma (note the generalized reduction in the extent of the lesion)

a b


a b





effects. Use of interferon-α16 is associated with the risk of hematologic and hepatic toxicity, hypothyroidism, depression, and neurotoxicity (spastic diplegia).17 The use of vincristine18

may lead to peripheral neuropathy, hematologic toxicity, and the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). Propranolol is a nonselective beta-blocker that has been used for several decades in cardiac, neurologic, endocrine, and other disorders. It is emerging as a promising treatment for IH.10 The effect of propranolol in IH was serendipitously discovered when two infants with hemangioma were treated with propranolol for cardiac complications while on corticosteroid treatment. Twenty-four hours after propranolol was initiated, the hemangioma appeared smaller and lighter in both children and was completely flat in one child by the age of 14 months.10 No rebound growth was noted on cessation of treatment in both children.10 After this initial report,10 many authors have reported the efficacy of propranolol for the treatment of IH.5,19-24

Propranolol has been used successfully in two cases of subglottic hemangioma associated with cutaneous hemangiomas that were resistant to standard treatments.25 Deep-seated lesions also respond to propranolol therapy. Fay et al.5 and Taban et al.26 reported the efficacy of treatment in patients with extensive orbital disease.

All four subjects in the current study showed a quick and intense response to therapy. One child showed a dramatic response within 24 hours. The lesion softened, changed color, and decreased in size, with improvement in ptosis. The youngest child was 3 months and the oldest 19 months at the time of initiating propranolol therapy. It is of interest to note that two of the four subjects had begun the proliferative phase for IH. These subjects had undergone unsuccessful steroid therapy previously. Three subjects had extensive periorbital lesions with orbital extension. After initiation of propranolol, there was a reduction in the size and extent of the lesions, and imaging studies confirmed the regression of the deeper lesions in all subjects.

The proposed mechanism of action of propranolol on IH includes vasoconstriction, apoptosis of capillary endothelial cells,27 and decreased production of vascular endothelial growth factor (VEGF) and fibroblastic growth factor (FGF). The latter is believed to occur through the down regulation of the RAF-mitogen-activated protein kinase pathway.28

Propranolol has been prescribed for decades in infants and is reported to be safe and well tolerated.29 However, in rare instances, the drug can cause deleterious adverse effects such as hypoglycemia, bradycardia, hypotension, and bronchospasm.30

High-output cardiac failure can occur in infants with very large hemangiomas, and PHACES syndrome. Ophthalmologists who are not familiar with use of propranolol need to be aware of these risks. Although some authors advise outpatient administration

of therapy,19 in order to avoid the few complications likely to occur with systemic propranolol, a strict pretherapy protocol is advisable.31 Our patients underwent comprehensive pediatric pretreatment examination and were admitted for 48 hours. Topical beta-blockers provide a safe and effective alternative to systemic therapy and are being investigated for use in the treatment of IH.32

Response to treatment can usually be determined by clinical examination (supplemented with photographs). However some lesions require imaging studies for accurate assessment. The earlier the onset of therapy during the proliferative phase, the more dramatic the response. Treatment is recommended until 1 year of age; the lesions rarely proliferate after this age. Gradual withdrawal through a tapering dose is recommended to avoid hyperadrenergic effects. However, we noted that even later initiation of therapy can have a beneficial effect. In such cases, therapy may be continued until no further regression is noted. At the time of writing, all subjects were still undergoing treatment and responding well.

In conclusion, we recommend the use of propranolol in all vision-threatening periorbital hemangiomas, provided there are no contraindications to its use. Although propranolol was safely used in the four subjects in this study, it is debatable if propranolol should be the first line of therapy for focal periorbital lesions, which are usually amenable to more standard protocols. Further studies with larger sample sizes are recommended to fully evaluate the safety, efficacy, and limitations of propranolol in the management of periocular IH.

ACKNOWLEDGMENT

We acknowledge with gratitude the contributions of all staff involved with patient care. We thank the families for their willing participation in the study.

REFERENCES

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6. Maguiness SM, Frieden IJ. Current management of infantile hemangiomas. Semin Cutan Med Surg 2010;29:106-14.

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8. Kushner BJ. Intralesional corticosteroid injection for infantile adnexal hemangioma. Am J Ophthalmol 1982;93:496-506.

9. Ranchod TM, Frieden IJ, Fredrick DR. Corticosteroid treatment of periorbital haemangioma of infancy: A review of the evidence. Br J Ophthalmol 2005;89:1134-8.

10. Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med 2008;358:2649-51.

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Cite this article as: Harikrishna B, Ganesh A, Al-Zuahibi S, Al-Jabri S, Al-Waily A, Al-Riyami A, et al. Oral propranolol for the treatment of periorbital infantile hemangioma: A preliminary report from Oman. Middle East Afr J Ophthalmol 2011;18:298-303.

Source of Support: Nil, Conflict of Interest: None declared.


Commentary

Serendipity, the humble case report and modern health science challenges

Any expecting parent would be devastated when their dear little infant is born with an unsightly periocular capillary

hemangioma. These tumors often present at birth or soon thereafter may be small and of no clinical significance. However, when they are large and unsightly, both parents and physicians are motivated to intervene therapeutically. Given their predilection for the upper lid, the risk of the mass precluding normal visual development is high. Sensory deprivation, induced astigmatism

and anisometropia contribute to the risk of developing amblyopia which is as high as 64%.1 All clinicians who treat these tumors are keenly aware of the inadequacies of conventional treatment modalities and for many years a need has existed for simpler and more effective therapies which have, until recently, evaded us.

It was therefore with great excitement and expectation that the landmark paper by Léauté-Labrèze et al, was received


AzharS

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