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Keywords:

  • β-adrenergic antagonist;
  • infantile haemangioma;
  • propranolol

Abstract

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Background:  Propranolol is a novel therapeutic agent in the treatment of cutaneous infantile haemangiomas. We assessed the effect of propranolol therapy in infantile haemangiomas of the orbit.

Methods:  A case series of four patients with orbital infantile haemangiomas were referred for management in our tertiary referral hospitals. Two of the patients had inadequate responses to prior corticosteroid therapy. One of the patients was commenced on propranolol at 2.5 years of age when the lesion was not in the proliferative phase. This represented the first case report of propranolol treatment for infantile haemangioma outside infancy. The other three children were in their infancy when propranolol was commenced. The patients were treated with oral propranolol.

Results:  All patients had significant improvement in their physical appearance, ocular examination findings and size of their lesions on radiological evaluation. No side-effects of propranolol treatment were observed.

Conclusions:  Propranolol is a promising treatment against infantile haemangiomas in the orbit, not only in infants but also in an older child with a stable lesion.


Introduction

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Infantile haemangiomas (IHs) are the most common childhood tumour.1 They are characteristically absent at birth and undergo a rapid phase of proliferation in infancy followed by a period of spontaneous involution over years.2 Although harmless in many cases, IHs can cause serious morbidity and mortality depending on their size and location. About 7% of IHs involve the orbit or eyelids,2 causing astigmatism, eyelid closure, strabismus and ultimately amblyopia.3 Corticosteroids are the current first-line treatment for disabling or life-threatening IHs,4 and a number of other rescue treatment options are available, all with serious and frequent side-effects.5

Propranolol is a non-selective adrenergic β-blocker. Léauté-Labrès et al.6 first reported a series of 11 children with cutaneous IHs treated with propranolol in the proliferative phase of growth, either as rescue therapy after corticosteroid failure or as first-line treatment. Marked regression of the IHs was observed in all eleven children.

We present four cases of IHs of the orbit treated successfully with propranolol. All patients had lesions with clinical histories and physical and radiological appearances characteristic of IHs. Two patients had failed prior corticosteroid therapy. Three patients were treated with oral propranolol in infancy, and one was treated later in childhood after the lesion had stabilized. In all patients, propranolol induced rapid and dramatic reduction in lesion size and improvement in ocular signs and symptoms. None of the patients experienced side-effects from propranolol.

This report illustrates the efficacy of propranolol in the treatment of IHs, not only in infants but also in older children. β-Adrenergic blockers have the potential to become the first-line treatment for IHs.

Methods

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Four patients with orbital lesions were referred to our tertiary hospitals for management of orbital lesions. Patient 1 was more than 2 years old at the time of referral, and all other patients were in their infancy. All patients presented with symptoms of either proptosis or eyelid swelling and closure, which were absent at birth but started and progressed rapidly in infancy. All patients had characteristic appearances of IHs on magnetic resonance imaging studies showing T2-hyperintense vascular lesions in the orbit containing flow voids (see Fig. 1). Two patients had prior corticosteroid treatment that either had partial (patient 1) or no (patient 2) effect on the lesions, and two others used propranolol as first-line therapy. The patients had various ocular abnormalities prior to propranolol therapy. Patient 1, the older child, had significant astigmatism and partial obstruction of her visual axis (see Fig. 2), resulting in amblyopia despite glasses and patching. Patient 2 had proptosis, lagophthalmos and astigmatism (see Fig. 5). Patients 3 and 4 had eyelid lesions obstructing visual axis.

image

Figure 1. T2-weighted magnetic resonance imaging scan through the orbits of Patient 1 showing a steroid-refractory left extraconal orbital infantile haemangioma at 20 months of age, compressing and distorting the left globe.

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image

Figure 2. Photograph of Patient 1 at two years and five months of age immediately before propranolol treatment, showing a steroid-refractory infantile haematoma in the left upper eyelid causing ptosis and partial obstruction of the visual axis.

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image

Figure 5. Photograph of Patient 2 at eleven weeks of age showing proptosis and displacement of the right globe by a steroid-refractory haemangioma.

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The patients were commenced on oral propranolol at low doses of 0.1 to 0.25 mg/kg/day in divided doses with inpatient monitoring of blood pressure and heart rate. The doses were escalated to 2 mg/kg/day over the subsequent fortnight. All four patients are currently continuing with long-term propranolol therapy. Patients were reviewed at regular intervals after commencement of propranolol. Patients' physical appearance, orthoptic assessment and ocular examination including visual acuity and refraction were noted at follow-up visits. Follow-up radiological imaging was obtained in three out of four patients to assess lesion size.

Informed consents were obtained from parents of all patients to publish their clinical details, including photographs. A waiver from ethics approval was obtained from the Ethics Committee at the Children's Hospital at Westmead for this publication.

Results

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

All patients had noticeable reduction of clinical symptoms and signs within a few days of commencement of propranolol therapy (see Table 1). The lesions continued to shrink on prolonged propranolol therapy. Eyelid swelling either significantly reduced or resolved, unblocking the visual axis (see Fig. 3). Proptosis and astigmatism improved. Three of the four patients had radiological imaging demonstrating marked reduction in size of the lesions after commencement of propranolol therapy. No side-effects were observed in any of the patients.

Table 1.  Patient characteristics, examination and investigations, propranolol treatment and outcome
Patient No.1234
Patient characteristics    
 SexFemaleFemaleFemaleMale
 Age lesion noticedEyelid discoloration at birth4 weeks8 weeks9 weeks
 Eye affectedLeftRightRightLeft
 SymptomsUpper eyelid swelling over weeks leading to eye closureProptosisUpper eyelid swelling leading to eye closureLower eyelid swelling leading to eye closure
 Corticosteroid therapyPrednisone 2 mg/kg/day at 8 weeks of age. Ceased at 7 months because of severe side-effectsPrednisone 2 mg/kg/day at 5 weeks of age. Weaned from 13 weeks of age because of successful treatment with propranololNilNil
 Clinical course prior to propranololLesion grew then stabilized on prednisoneLesion grew despite prednisoneLesion stabilized after initial growthLesion was increasing in size
Examination and investigation findings prior to propranolol
 Ocular abnormalities on examinationEyelid closure, astigmatism, amblyopia despite glasses and patching. Refraction 0 DS/+4.50 DC. See Fig. 2Proptosis, globe displacement, lagophthalmos. Refraction +2.00 DS/+3.50 DC. See Fig. 5Eyelid closure. Refraction +1.00 DS/+1.00 DCEyelid closure, variable alignment. Refraction +2.50 DS
 Magnetic resonance imaging appearancesExtraconal lesion, dimension 20 × 30 × 33 mm, T1- and T2-hyperintense, flow voids. See Fig. 1Retrobulbar and extraconal lesion displacing optic nerve and lateral rectus, dimension 30 × 15 × 25 mm, T1- and T2-hyperintense, flow voids. See Fig. 4Extraconal lesion, dimension 26 × 10 × 28 mm, T2-hyperintense, flow voidsExtraconal and lower eyelid lesion, dimension 15 × 10 × 13 mm, T2-hyperintense, flow voids
Propranolol treatment    
 Age of propranolol commencement2 years and 5 months11 weeks5 months15 weeks
 Dose of propranolol2 mg/kg/day0.25 then 2 mg/kg/day0.1 then 0.3 then 2 mg/kg/day0.2 then 0.5 then 2 mg/kg/day
 Length of treatment (at November 2009)12 months and continuing14 months and continuing6 months and continuing7 months and continuing
Effect of propranolol    
 Initial clinical observations upon commencementSwelling and ptosis improved within daysProptosis decreased within days of low-dose propranololSwelling decreased within 4 days of low-dose propranolol. Eyes opened moreSwelling decreased within days of low-dose propranolol
 Size of infantile haemangioma on radiological imaging post propranolol (time after commencement of propranolol)12 × 12 × 10 mm (6 months)Not available8 × 12 × 10 mm (2.5 months)13 × 9 × 7 mm (6 months)
 Ocular examinations on propranolol (time after commencement of propranolol)Minimal eyelid swelling, some improvement in visual acuity, refraction 0 DS/+2.50 DC (4 months). See Fig. 3Minimal proptosis (1 month). Refraction 0 DS/2.50 DC (8 months). See Fig. 6Minimal lid swelling. Otherwise normal. Refraction 1.5 DS/0.5 DC (2.5 months)Lesion no longer noticeable clinically. Nil abnormality. (2 months)
 Side-effectsNilNilNilNil
image

Figure 4. Axial image of T2-weighted magnetic resonance imaging scan through the orbits of Patient 2 at five weeks of age, showing a right-sided intra- and extra-conal haemangioma displacing the globe.

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image

Figure 6. Photograph of Patient 2 at eleven weeks of age showing proptosis and displacement of the right globe by a steroid-refractory haemangioma.

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image

Figure 3. Photograph of Patient 1 at three years of age, six months into propranolol treatment. The left upper eyelid had almost reverted to normal curvature and minimal residual ptosis remained.

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Discussion

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References

Infantile haemangiomas are common childhood tumours1 associated with premature birth7 and retinopathy of prematurity.8 The pathogenesis of these lesions is unclear.9–12 They are apparently absent or very small at birth but undergo a phase of rapid growth for several months after birth, followed by a period of spontaneous slow involution over months or years.13 On Doppler ultrasound they appear as highly vascular masses with marked intralesional flow, and on magnetic resonance imaging scan they are moderately hyperintense on T2-weighted images with flow voids.14 Although not malignant in histological appearances, IHs can cause serious mortality and morbidity depending on their size and location.15 About 7% of IHs involve the orbit or eyelids,2 resulting in astigmatism, eyelid closure, proptosis, exophthalmos, strabismus, lacrimal duct obstruction and ultimately amblyopia.3

Corticosteroids, either systemic or intralesional, are the current first-line treatment for disabling or life-threatening IHs.4 About 50–90% of IHs treated with systemic corticosteroids stabilize or shrink, a significant proportion of patients experience side-effects and 20–60% of lesions rebound after cessation of steroids.4 Intralesional injection of corticosteroids into orbital IHs can be effective16 but carries a significant risk of retinal artery embolization.17,18 For steroid-refractory IHs, a number of alternative treatments are available, including interferon-α 2a and 2b,19 bleomycin,20 vincristine,21 cyclophosphamide,22 thalidomide23 and lanreotide.24 However, these treatments are associated with frequent and serious adverse effects and are therefore reserved for life-threatening lesions.5 Surgical excision of orbital IHs is usually reserved for lesions refractory to medical treatment25,26 as surgery carries significant risks and complications such as bleeding.

Propranolol is a non-selective adrenergic β-blocker used for migraine prophylaxis,27 heart failure28 and hypertension29 in children. In 2008, Léauté-Labrès et al.6 reported a case series of 11 infants with IHs successfully treated with propranolol after serendipitously observing regression of cutaneous IHs in two infants treated with propranolol for cardiac conditions. All the lesions were in the proliferative phase, some failed prior corticosteroid treatment, and some used propranolol as a first-line therapy. In all cases, change of colour and softening of the lesions were observed within 24 h of initial propranolol administration, and the lesions continued to flatten with treatment. Most of the lesions stabilized or resolved when propranolol was ceased. In two out of 10 patients, there was mild rebound growth of the lesions after cessation of propranolol, but both eventually stabilized. Side-effects were not mentioned in the report, but in a follow-up report,30 mild and self-limiting side-effects were noted in a small proportion of children treated.

We report four cases of steroid-refractory orbital IHs treated successfully with propranolol. We did not obtain biopsies of the lesions because of bleeding risk, but the clinical history and radiological findings were characteristic of IHs. The lesions in all cases threatened vision because of blockage of visual axis, proptosis or astigmatism. Two of the children failed prior corticosteroid therapy. In all cases, regression of the lesions was observed within a few days of commencing propranolol. The lesions continued to shrink on long-term propranolol therapy, resulting in significant amelioration or complete resolution of visual symptoms and signs and sparing the children from further medical and surgical interventions. Radiological evaluation showed shrinkage of lesions after propranolol therapy. Significantly, case 1 was started on propranolol at two and half years of age and represents the first case report of successful propranolol treatment of IHs in an older child outside the proliferative phase in infancy. None of the patients suffered any side-effects. This reflects our institutional experience of treating more than 25 IHs at various other anatomical sites to date with propranolol without serious adverse effects (E McCahon, pers. comm., 2009) Therefore, propranolol appears to be a promising treatment of IHs.

The therapeutic mechanism of action of propranolol on IHs is unclear. In all four cases, we observed rapid initial shrinkage of the lesions even with very small doses of propranolol. Léauté-Labrès et al. also observed reduction in the colour and fullness of the lesions within 24 h of initial propranolol administration.6 Such a rapid effect is likely to be due to peripheral vasoconstriction mediated by direct blocking of the β2-adrenergic receptor. Indeed, β-adrenergic antagonists are well known to cause peripheral vasoconstriction.31,32 However, whether or how this leads to sustained regression of the lesions is unknown. If a centrally inert and peripherally active β-adrenergic blocker was available for clinical trial, many of the potential side-effects of propranolol could be obviated.

We report four cases of corticosteroid-refractory IHs of the orbit successfully treated with propranolol, including the first report of treatment outside the proliferative phase of the tumour in an older child outside infancy. The vision-threatening lesions showed rapid and sustained response to propranolol, with concomitant visual improvement and no adverse effects. Although the mechanism of action still requires elucidation, β-adrenergic antagonists may become the first-line treatment for IHs if their efficacy and safety are further established.

References

  1. Top of page
  2. A
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. References
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