Dermatologic Therapy, Vol. ••, 2014, ••–•• Printed in the United States · All rights reserved
© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Episcleral infantile hemangioma successfully treated with topical timolol Cristina Ciudad Blanco*, Minia Campos Domínguez*, Basilio Moreno García†, Cándida Ana Villanueva Álvarez-Santullano*, Beatriz Berenguer Fröhner‡ & Ricardo Suárez Fernández* Departments of *Dermatology, †Ophthalmology and ‡Pediatric Plastic Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
ABSTRACT: Episcleral hemangiomas are usually associated with neonatal hemangiomatosis. Recently, propranolol has been described for the treatment of this entity. We present for the first time a patient with an episcleral hemangioma without neonatal hemangiomatosis successfully treated with topical timolol. KEYWORDS: episcleral hemangioma, infantile hemangioma, topical timolol
Introduction Episcleral hemangiomas are rare. They are mostly reported in patients with neonatal hemangiomatosis. They are uncommon as an isolated finding. They may originate from the episcleral vascular tissues. Early treatment is advisable in order to avoid ocular complications.
Case report A 5-month-old girl was referred for the evaluation of an ocular lesion that had appeared in the first week of her life. Her mother was diabetic and she
Address correspondence and reprint requests to: Minia Campos Domínguez, MD, Department of Dermatology, Hospital General Universitario Gregorio Marañón, C/Doctor Esquerdo 46, CP 28007 Madrid, Spain, or email: [email protected].
developed intrauterine growth restriction and low weight at birth. Her family had noticed other two vascular lesions on her body that had been seen shortly after birth. Physical examination revealed a 6-mm red papule on the episclera of her right eye (Fig. 1) and other two violaceous-red plaques on her left thigh and on her right scapula. Ophthalmologic evaluation did not reveal any ocular complications. Abdominal and transfontanelar ultrasound were completely normal. Ocular magnetic resonance imaging showed a 10 × 2 mm highly vascularized episcleral lesion and the diagnosis of infantile hemangioma was made (Fig. 2). Decision to treat was based on active growing and ophthalmic risk (high intraocular pressure, neoangiogenesis). Cardiorespiratory evaluation was completely normal. The first two days, timolol was administered at the hospital under close monitoring. No hypotension, bradycardia, or hypoglycemia was observed, so parents were instructed to apply timolol maleate 0.5% ophthalmic solution twice a day. After 3 weeks of
1
Ciudad Blanco et al.
FIG. 3. Almost complete clearance of the hemangioma after FIG. 1. Episcleral hemangioma: a 6-mm red papule on the
5 months of treatment.
episclera of the right eye.
FIG. 2. Ocular magnetic resonance imaging showed a 10 × 2 mm highly vascularized episcleral lesion.
treatment, the hemangioma was lighter in terms of color and significantly reduced in size and thickness. Treatment was extended by 5 months with almost complete clearance of the hemangioma (Fig. 3). During follow-up, the patient had a close clinical monitoring. The treatment was well tolerated and the family did not refer any adverse effects such as local burning, stinging, or irritant reactions. After treatment discontinuation at 12 months, rebound growth of the episcleral hemangioma was not observed.
Discussion Vascular malformations are usually present at birth. Infantile hemangiomas appear the first weeks of life, as in our patient. She had other two infantile hemangiomas on her body. After treat-
2
ment with topical timolol, the episcleral hemangioma regressed. The other two hemangiomas were not treated. The treatment was stopped when the patient was 10-month old because the episcleral lesion was almost clear, and the other two infantile hemangiomas did not show any change. This was in keeping with natural evolution of infantile hemangiomas. The other infantile hemangiomas on her body were useful as a control for the episcleral hemangioma. Several cases in the literature report successful treatment of periocular infantile hemangiomas (1–6). However, there are only a few reports on the treatment of episcleral hemangiomas (6). Possible complications of ocular hemangiomas include amblyopia, strabismus, proptosis, glaucoma, optic nerve atrophy, and lacrimal duct occlusion (4,7). In order to avoid such complications, an early treatment is advisable. Both systemic or intralesional corticosteroids and surgery have been used with vision-threatening complications and suboptimal results (2,8). Beta-blockers have become the firstline treatment for periorbital hemangiomas due to their efficacy and low adverse event profile (9). A single case of an episcleral hemangioma successfully treated with oral propanolol has been reported (7). Systemic adverse effects of beta-blockers are well known and include bronchospasm, heart block, hypotension, bradycardia, congestive heart failure, and hypoglycemia (3). Children treated with oral propranolol must be closely monitored, so theoretically topical betablocker might be a safe and effective alternative in thin and flat hemangiomas (4). One of these topical beta-blockers is timolol. It is a nonselective beta-blocker similar to propranolol that is available as a topical solution in concentrations of 0.25% and 0.5% or as a gel in concentrations of 0.1% and 0.5% for treatment
Episcleral hemangioma treated with timolol
of glaucoma (10). It has been successfully used for the treatment of thin and superficial infantile hemangiomas on skin and mucosa, including those located in the eyelid (3–6,11–13). The mechanism of action is not clear, but it may probably be the same as for propanolol (4). Initial effects of systemic beta-blockers which appear within 1–3 days after starting the therapy are due to vasoconstriction. Both decreased vascular endothelial growth factor expression, and induction of endothelial cell apoptosis may be involved. Systemic absorption following topical application of timolol in hemangiomas has not been studied yet. It has been suggested that it could depend on the thickness and size of the hemangioma and on the presence of ulceration. Based on the evidence to date about systemic absorption of other topical medications, using timolol on mucosa, on thinner skin sites, and in ulcerated hemangiomas may further increase systemic absorption (10,14). Absorption is higher in ocular mucosa than in normal skin (10). Besides, timolol can drain through the nasolacrimal duct and be absorbed by the ocular and nasopharyngeal mucosa. Therefore, it is possible to expect a larger number of systemic side effects using topical drugs through mucosal surfaces. Adverse reactions with ocular timolol for pediatric glaucoma have been described and include drowsiness, bradycardia, itching sensation, apneic spells, and asthma exacerbations (10). Consequently, systemic or topical beta-blockers should be used with caution in patients with a personal history of asthma or cardiopulmonary disease. The major advantages of topical timolol include ready availability, low cost, ease of administration, and minimal risk of drug-related adverse events (12). On balance, topical timolol could be an effective and safe alternative treatment for superficial infantile hemangiomas located on skin and mucosal surfaces. However, we have to highlight that topical timolol for infantile hemangiomas is an off-label use. Until we have more experience with the use of this drug for this indication, objective clinical measurements should be used as guides in determining the optimal dosage for each patient. Heart rate and blood pressure can be used as indicators to monitor the patient (10). We would like to note that treatment of scleral hemangiomas requires an individualized approach. It is advisable to be more cautious about patients with history of
cardiorespiratory disorders. Further prospective studies are required to determine the safety and efficacy of topical timolol.
Conflict of interest No conflict of interest for any author.
References 1. Snir M, Reich U, Siegel R, et al. Refractive and structural changes in infantile periocular capillary haemangioma treated with propranolol. Eye 2011: 25: 1627–1634. 2. Hernandez JA, Chia A, Quah BL, Seah LL. Periocular capillary hemangioma management practices in recent years. Clin Ophthalmol 2013: 7: 1227–1232. 3. Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol 2010: 128: 255–256. 4. Ni N, Langer P, Wagner R, et al. Topical timolol for periocular hemangioma: report of further study. Arch Ophthalmol 2011: 129: 377–379. 5. Xue K, Hildebrand GD. Topical timolol maleate 0.5% for infantile capillary hemangioma of the eyelid. Br J Ophthalmol 2012: 96: 1536–1537. 6. Calvo M, García-Millán C, Villegas C, Fueyo-Casado A, Burón I. Topical timolol for infantile hemangioma of the eyelid. Int J Dermatol 2013: 52: 603–604. 7. Berk DR, Culican SM, Bayliss SJ. Scleral hemangioma: case report and response to propanolol. Pediatr Dermatol 2013: 20: 16–17. 8. Craiglow BG, Antaya RJ. Management of infantile hemangiomas: current and potential pharmacotherapeutic approaches. Paediatr Drugs 2013: 15: 133–138. 9. Levitt M, Coumou AD, Groeneveld L, Freling NJ, van der Horst CM, Saeed P. Propranolol as first-line treatment in orbital infantile haemangiomas: a case series. Orbit 2014: 33: 178–183. 10. McMahon O, Oza V, Fireden IJ. Topical timolol por infantile hemangiomas: putting a note of caution in “cautiously optimistic”. Pediatr Dermatol 2012: 29: 127–130. 11. Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol 2010: 146: 564– 565. 12. Chakkittakandiyil A, Phillips R, Frieden IJ, et al. Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study. Pediatr Dermatol 2012: 29: 28–31. 13. Semkova K, Kazandjieva J. Topical timolol maleate for treatment of infantile haemangiomas: preliminary results of a prospective study. Clin Exp Dermatol 2013: 38: 143–146. 14. Chantasart D, Hao J, Li SK. Evaluation of skin permeation of β-blockers for topical drug delivery. Pharm Res 2013: 30: 866–877.
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© 2014 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY ISSN 1396-0296
THERAPEUTIC HOTLINE Episcleral infantile hemangioma successfully treated with topical timolol Cristina Ciudad Blanco*, Minia Campos Domínguez*, Basilio Moreno García†, Cándida Ana Villanueva Álvarez-Santullano*, Beatriz Berenguer Fröhner‡ & Ricardo Suárez Fernández* Departments of *Dermatology, †Ophthalmology and ‡Pediatric Plastic Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
ABSTRACT: Episcleral hemangiomas are usually associated with neonatal hemangiomatosis. Recently, propranolol has been described for the treatment of this entity. We present for the first time a patient with an episcleral hemangioma without neonatal hemangiomatosis successfully treated with topical timolol. KEYWORDS: episcleral hemangioma, infantile hemangioma, topical timolol
Introduction Episcleral hemangiomas are rare. They are mostly reported in patients with neonatal hemangiomatosis. They are uncommon as an isolated finding. They may originate from the episcleral vascular tissues. Early treatment is advisable in order to avoid ocular complications.
Case report A 5-month-old girl was referred for the evaluation of an ocular lesion that had appeared in the first week of her life. Her mother was diabetic and she
Address correspondence and reprint requests to: Minia Campos Domínguez, MD, Department of Dermatology, Hospital General Universitario Gregorio Marañón, C/Doctor Esquerdo 46, CP 28007 Madrid, Spain, or email: [email protected].
developed intrauterine growth restriction and low weight at birth. Her family had noticed other two vascular lesions on her body that had been seen shortly after birth. Physical examination revealed a 6-mm red papule on the episclera of her right eye (Fig. 1) and other two violaceous-red plaques on her left thigh and on her right scapula. Ophthalmologic evaluation did not reveal any ocular complications. Abdominal and transfontanelar ultrasound were completely normal. Ocular magnetic resonance imaging showed a 10 × 2 mm highly vascularized episcleral lesion and the diagnosis of infantile hemangioma was made (Fig. 2). Decision to treat was based on active growing and ophthalmic risk (high intraocular pressure, neoangiogenesis). Cardiorespiratory evaluation was completely normal. The first two days, timolol was administered at the hospital under close monitoring. No hypotension, bradycardia, or hypoglycemia was observed, so parents were instructed to apply timolol maleate 0.5% ophthalmic solution twice a day. After 3 weeks of
1
Ciudad Blanco et al.
FIG. 3. Almost complete clearance of the hemangioma after FIG. 1. Episcleral hemangioma: a 6-mm red papule on the
5 months of treatment.
episclera of the right eye.
FIG. 2. Ocular magnetic resonance imaging showed a 10 × 2 mm highly vascularized episcleral lesion.
treatment, the hemangioma was lighter in terms of color and significantly reduced in size and thickness. Treatment was extended by 5 months with almost complete clearance of the hemangioma (Fig. 3). During follow-up, the patient had a close clinical monitoring. The treatment was well tolerated and the family did not refer any adverse effects such as local burning, stinging, or irritant reactions. After treatment discontinuation at 12 months, rebound growth of the episcleral hemangioma was not observed.
Discussion Vascular malformations are usually present at birth. Infantile hemangiomas appear the first weeks of life, as in our patient. She had other two infantile hemangiomas on her body. After treat-
2
ment with topical timolol, the episcleral hemangioma regressed. The other two hemangiomas were not treated. The treatment was stopped when the patient was 10-month old because the episcleral lesion was almost clear, and the other two infantile hemangiomas did not show any change. This was in keeping with natural evolution of infantile hemangiomas. The other infantile hemangiomas on her body were useful as a control for the episcleral hemangioma. Several cases in the literature report successful treatment of periocular infantile hemangiomas (1–6). However, there are only a few reports on the treatment of episcleral hemangiomas (6). Possible complications of ocular hemangiomas include amblyopia, strabismus, proptosis, glaucoma, optic nerve atrophy, and lacrimal duct occlusion (4,7). In order to avoid such complications, an early treatment is advisable. Both systemic or intralesional corticosteroids and surgery have been used with vision-threatening complications and suboptimal results (2,8). Beta-blockers have become the firstline treatment for periorbital hemangiomas due to their efficacy and low adverse event profile (9). A single case of an episcleral hemangioma successfully treated with oral propanolol has been reported (7). Systemic adverse effects of beta-blockers are well known and include bronchospasm, heart block, hypotension, bradycardia, congestive heart failure, and hypoglycemia (3). Children treated with oral propranolol must be closely monitored, so theoretically topical betablocker might be a safe and effective alternative in thin and flat hemangiomas (4). One of these topical beta-blockers is timolol. It is a nonselective beta-blocker similar to propranolol that is available as a topical solution in concentrations of 0.25% and 0.5% or as a gel in concentrations of 0.1% and 0.5% for treatment
Episcleral hemangioma treated with timolol
of glaucoma (10). It has been successfully used for the treatment of thin and superficial infantile hemangiomas on skin and mucosa, including those located in the eyelid (3–6,11–13). The mechanism of action is not clear, but it may probably be the same as for propanolol (4). Initial effects of systemic beta-blockers which appear within 1–3 days after starting the therapy are due to vasoconstriction. Both decreased vascular endothelial growth factor expression, and induction of endothelial cell apoptosis may be involved. Systemic absorption following topical application of timolol in hemangiomas has not been studied yet. It has been suggested that it could depend on the thickness and size of the hemangioma and on the presence of ulceration. Based on the evidence to date about systemic absorption of other topical medications, using timolol on mucosa, on thinner skin sites, and in ulcerated hemangiomas may further increase systemic absorption (10,14). Absorption is higher in ocular mucosa than in normal skin (10). Besides, timolol can drain through the nasolacrimal duct and be absorbed by the ocular and nasopharyngeal mucosa. Therefore, it is possible to expect a larger number of systemic side effects using topical drugs through mucosal surfaces. Adverse reactions with ocular timolol for pediatric glaucoma have been described and include drowsiness, bradycardia, itching sensation, apneic spells, and asthma exacerbations (10). Consequently, systemic or topical beta-blockers should be used with caution in patients with a personal history of asthma or cardiopulmonary disease. The major advantages of topical timolol include ready availability, low cost, ease of administration, and minimal risk of drug-related adverse events (12). On balance, topical timolol could be an effective and safe alternative treatment for superficial infantile hemangiomas located on skin and mucosal surfaces. However, we have to highlight that topical timolol for infantile hemangiomas is an off-label use. Until we have more experience with the use of this drug for this indication, objective clinical measurements should be used as guides in determining the optimal dosage for each patient. Heart rate and blood pressure can be used as indicators to monitor the patient (10). We would like to note that treatment of scleral hemangiomas requires an individualized approach. It is advisable to be more cautious about patients with history of
cardiorespiratory disorders. Further prospective studies are required to determine the safety and efficacy of topical timolol.
Conflict of interest No conflict of interest for any author.
References 1. Snir M, Reich U, Siegel R, et al. Refractive and structural changes in infantile periocular capillary haemangioma treated with propranolol. Eye 2011: 25: 1627–1634. 2. Hernandez JA, Chia A, Quah BL, Seah LL. Periocular capillary hemangioma management practices in recent years. Clin Ophthalmol 2013: 7: 1227–1232. 3. Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol 2010: 128: 255–256. 4. Ni N, Langer P, Wagner R, et al. Topical timolol for periocular hemangioma: report of further study. Arch Ophthalmol 2011: 129: 377–379. 5. Xue K, Hildebrand GD. Topical timolol maleate 0.5% for infantile capillary hemangioma of the eyelid. Br J Ophthalmol 2012: 96: 1536–1537. 6. Calvo M, García-Millán C, Villegas C, Fueyo-Casado A, Burón I. Topical timolol for infantile hemangioma of the eyelid. Int J Dermatol 2013: 52: 603–604. 7. Berk DR, Culican SM, Bayliss SJ. Scleral hemangioma: case report and response to propanolol. Pediatr Dermatol 2013: 20: 16–17. 8. Craiglow BG, Antaya RJ. Management of infantile hemangiomas: current and potential pharmacotherapeutic approaches. Paediatr Drugs 2013: 15: 133–138. 9. Levitt M, Coumou AD, Groeneveld L, Freling NJ, van der Horst CM, Saeed P. Propranolol as first-line treatment in orbital infantile haemangiomas: a case series. Orbit 2014: 33: 178–183. 10. McMahon O, Oza V, Fireden IJ. Topical timolol por infantile hemangiomas: putting a note of caution in “cautiously optimistic”. Pediatr Dermatol 2012: 29: 127–130. 11. Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol 2010: 146: 564– 565. 12. Chakkittakandiyil A, Phillips R, Frieden IJ, et al. Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study. Pediatr Dermatol 2012: 29: 28–31. 13. Semkova K, Kazandjieva J. Topical timolol maleate for treatment of infantile haemangiomas: preliminary results of a prospective study. Clin Exp Dermatol 2013: 38: 143–146. 14. Chantasart D, Hao J, Li SK. Evaluation of skin permeation of β-blockers for topical drug delivery. Pharm Res 2013: 30: 866–877.
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