Efficacy of Topical Β Blockers (0,25% Timolol Maleate Eye Drops

)

in Treatment of Infantile Hemangioma

Wizar Putri Mellaratna

1 *

, Deryne Anggia Paramita

Department of Dermato-Venereology, Faculty of Medicine Universitas Sumatera Utara, Dr, Mansur Street number 5,

Padang Bulan, Medan

Keywords: Infantile hemangioma, timolol maleate, eye drops, topical therapy

Abstract: Introduction: Infantile hemangioma (IH) is a benign vascular tumor, that occurs several weeks after birth.

Pathogenesis of IH considers an escalation of angiogenesis, vasculogenesis in proliferative phases and

apoptosis in regression phases. Since 2010, topical timolol maleate has used as a treatment of superficial

and non-ulcerated IH. Case: A 2 months 25 days infant admitted to our hospital with a history of bright red

swelling on his left forehead. The lesion appeared first like a mosquito bite swelling when the patient was

three weeks old, then lesion enlarged and the color became more erythematous.Dermatology examination

indicated solitaryerythematous nodule, size 0,7x0,3x0,05 cm

, stepping border, and cobblestone surface,

rubbery consistency, and warm on left temporal. The hemangioma severity scale (HSS) was six, and

hemangioma dynamic complication scale (HDCS) was 0. The patient was treated with topical β blocker

timolol maleate eye drop 0,25%

, one drop twice a day.Three months after treatment, the regression of the

lesion was significantwith size 0,5x0,1x0,01 cm

. Discussion: Topical β blocker indicated in our caseto

reduce the risk of functional compromise such as ulceration, scar, and risk for residual skin development

include telangiectasia, redundant skin, and fibrofatty tissue after involution phases. Timolol maleate 0,25%

1 drops two times a day resulted in regression of superficial IH, topical and lower concentration used

reduces the risk of side effects. Conclusions: Importance to determine the effective treatment for IH based

on some points include anatomic depth, morphology, and risk for complication, functional compromise, and

permanent disfigurement.

1 INTRODUCTION

Infantile hemangioma (IH) is a benign vascular

tumor characterized by increased endothelial

proliferation and epidermal turnover. Incidence of

IH approximately 5-10%, more common among

female infants, with female to male ratios

3:1.Although they occur in all races, IH is more

common in Caucasian (Laranjo et al, 2014). Based

on a prospective study of IH by Dickson, the risk

factors that strongly associated with IH are

premature infants, low birth babies (< 2500 gram),

babies conceived invitro fertilization (IVF), the

family history of IH (62,6%) ( Dickison et al, 2011).

Pathogenesis of IH have considered an escalation of

angiogenesis and vasculogenesis, and upregulated

expression of glucose transporter protein type-1

(GLUT-1), vascular endothelial growth factor

(VEGF), and fibroblast growth factor (FGF). GLUT-

1 is a specific marker for IH.Two phases of IH

include proliferation and involution. Proliferation

occurs several weeks after birth, characterized by

quick proliferation of endothelial cell and involution

starts by one year of age, characterize by reducing of

proliferation, increase apoptosis, and most lesions

flatten and shrink from the center outward (Callahan

et al, 2012).

Treatment of IH with systemic propranolol first

described by Leaute-Labreze et al. in 2008,

hypothesized mechanisms of action are decreased

nitrite oxide, vasoconstriction, blockage of VEGF

and FGF, and stimulation of apoptosis causing IH

regression (Chambers et al, 2012). Recently,

propranolol has become the first-line treatment for

complicated IH. Topical timolol maleate as a

nonselective β blocker agent, since February 2010,

has been reported as treatment of superficial and

non-ulcerated IH. Some studies report tumor

reduction up to 100% in superficial IH by using

timolol maleate 0,5%, 0,25% and propranolol 1%.

Efﬁcacy of Topical Blockers (0,25 .

DOI: 10.5220/0009991404550459

In Proceedings of the 2nd International Conference on Tropical Medicine and Infectious Disease (ICTROMI 2019), pages 455-459

ISBN: 978-989-758-469-5

455

Most previous studies described no systemic or only

minimal systemic absorption of topical β blocker,

but only one report by Weibel et al. concluded that

topical timolol is systemically absorbed, but the

impact of low serum timolol is not well studied

(Weibel et al, 2016). Here we report a case of IH

that was successfully treated with topical β blocker.

2 CASE

A 2 months 25 days old infant was admitted to our

hospital with two months history of bright red

swelling on his left forehead. The lesion appeared

first like a mosquito bite swelling, with a pale color

on the left forehead when the patient was three

weeks old, then lesion enlarged, became more

elevated with strawberry-like color. Baby’s birth

weight was 3,1 kg. Maternal pregnancy history

wasstandard. His father’s sister also had the same

history as a patient. Physical examination revealed

the patient was alert, and other vital signs were

typical. There was no abnormality of the airway,

cardiovascular, ocular, and motor movements of the

patient. The current baby’s weight was 5,1 kg.

Dermatology examination indicated

solitaryerythematous nodule with size 0,7x0,3x0,05

, stepping border, and cobblestone surface,

rubbery consistency on left forehead. Here is the

photo of the patient on the first visit.

Picture 1: Inspection: solitary erythematous nodule, size 0,7x0,3x0,05 cm3, stepping border, cobblestone surfaceon left

temporal. Palpation: Cobblestone surface, rubbery consistency, fixed and warm.

Examination results of IH severity using

hemangioma severity scale (HSS) and the risk of IH

complication using hemangioma dynamic

complication scale (HDCS) indicated:

Table 1. Results of HSS and HDCS

HSS HDCS

Parameter Score

Objective items

Infection 0

Size (≤ 1 cm) 1 Ulceration 0

Location (peripheral face) 3 Feeding difficulties 0

Risk for associated structural anomalies 0 Torticollis 0

Complication 0 Cartilage distortion or destruction 0

Subjective items

Airway involvement 0

Pain 0 Visual compromise 0

Risk of disfigurement (telangiectasia) 2 Hypothyroidism 0

Anemia 0

Congestive heart failure 0

GI bleed 0

Hepatic dysfunction 0

TOTAL 6 TOTAL 0

The table was quoted with a little modification

from references number 9 and 10.

Differential diagnoses of this patient are an

infantile hemangioma, congenital hemangioma, and

pyogenic granuloma. Clinical diagnosis is infantile

hemangioma, and the patient was treated with

topical β blocker timolol maleate eye drop 0,25%

one drop twice a day. In addition, parents were

456

educated about a sign of hypothermia, bradycardia,

hypotension, hypoglycemia, and encouragethem to

feed the infant before each dose and do not

administer before bedtime without feeding. The

progress of this patient was followed monthly by a

dermatologist (to see the regression of the lesions)

and by a pediatrician (evaluating the

cardiopulmonary function and hypoglycemia).

One month after treatment, lesion became

smaller and lighter in color with size was

0,7x0,3x0,03 cm

, and the treatment was

stillcontinued because there were a good response

and no adverse effects. Two months from the first

visit, the size of the lesion was regressed, and the

size was 0,7x0,03x0,01, and there were no adverse

effects detected. Three months from the initial visit,

the regression of the lesion was more significant

with the current size was 0,5x0,1x0,01 cm

, and

there was no adverse effect occurred. Here is the

photograph of the patient in the last control:

Picture 2: Inspection: solitary pale erythematous nodule, size 0,5x0,1x0,01 cm3, firm border, pale on left temporal.

Palpation: smooth surface, rubbery consistency, fixed and warm nodules

Prognosis of this patient was considered suitable

because there were no systemic involvement, no risk

of complication or structural anomaly, and

permanent disfigurement.

3 DISCUSSION

Infantile hemangioma usually develops on the first 3

or 4 weeks of life. Phases of IH are proliferative and

involution. IH proliferate time depending on

morphology and configuration. Most growth is

completed by around five months.Clinical

appearance of IH in proliferative phases is

enlargement, elevated, with rubbery consistency,

surrounding pallor, and dilatation of surrounding

veins.The involution phases range from 1 year until

5-7 years of age, characterize by fading of the shiny

crimson color to a dull purplish hue, the surface

showed tiny white freckles, lesions softens, affected

skin becomes slightly wrinkled (Painter et al,

2019;Moyakine et al,2019).

In our case patient was

still in proliferative phases with typically red

noduleand rubbery consistency.

Based on lesion distribution and anatomic depth,

IH is classified into superficial, deep, and compound

type. Superficial IH describes as bright red papules,

plaques or nodule which are warm to touch,non-

tender with cobblestone or smooth surface, and also

known as strawberry type. Deep IH is lesion from

reticular dermis extends to subcutaneous tissues,

characterized by blue, appears as flesh-colored to

blue masses that are warm to touch. The mixed type

has no characteristics of superficial and deep IH. In

our cases, the patient showed superficial IH with

bright red nodule and warm to touch. Morphological

classification of IH is localized, segmental,

indeterminate, and multifocal. This classification is

often associated with some internal complications

and functional compromise. The localized lesion is

solitary discrete lesion and typically circular.

Segmental IH involves broad anatomic region, often

unilateral, and sharply demarcated. Segmental IH

has higher rate complication and increases the risk

for functional compromise if located on the face, it

is often associated with PHACE syndrome, and if it

is located on the lumbosacral and anogenital region,

is associated with LUMBAR syndrome. Multifocal

is numerous lesions (more than 10), discrete,

localized lesions present at more than one anatomic

sites and often associated with hepatic

hemangiomatosis. Indeterminate lesions are

notcharacterized as localized or

segmental.(Haggstrom et al,2019) In our case, this

patient has a localized IH with located in temporal

region, revealed a solitary nodule with size is less

than 1 cm, only superficial involvement based on the

erythematous color of the lesion, so there was no

risk for complication and functional compromise

according to location, morphology and anatomic

depth of the lesion.

Efﬁcacy of Topical Blockers (0,25

457

The score of HSS and HDCS indicate outcome

measure, HSS measures the severity of lesion while

the HDCS assigns a grade for each complication in a

longitudinal use. Complication assed in HSS is

correlated with HDCS grade. Both of the scale

measure size changes, complications, and risk for

disfigurement. Study of Moyakine in 2017,

determined using HSS to facilitate treatment

decisions for IH, scores of 11 or higher as a marker

for propranolol treatment, scores of 6 or lower as a

marker for watchful waiting or topical β blocker

treatment, and children with HSS score higher than 6

and lower than 11, treatment decision should

consider other factors, including patient age, IH

type, and parental preferences.(Zheng et

al,2019;Rotter et al,2017) In our case, the HSS was

six, and HDCS was 0, based on HSS results, the

patient was treated with topical β blocker.

Diagnosis IH is based on clinical examination

and history. USG, MRI, and CT scan are only

required if there is systemic involvement. IH should

be differentiated with other vascular anomalies such

as congenital hemangioma and pyogenic granuloma.

This lesion occurred three weeks after birth, and the

lesion was rapidly progressed to eliminate the

diagnosis of congenital hemangioma. Location on

the face, tumor with red to brownish red color

manifested in pyogenic granuloma and IH, but

because in our case the lesion occurredseveral weeks

after birth and the surface of the lesion was not

easily bleeds and ulcerated, favor diagnosis as IH.

Treatment of IH has a purpose of preventing

complication, functional compromise, and

permanent disfigurement for this patient. In our case,

the lesion was superficial and localized, so the

primary purpose of administered treatment for this

patient was to reduce the risk of functional

compromise such as ulceration and scar and risk for

residual skin development include telangiectasia,

redundant skin, and fibrofatty tissue after involution

phases. Previous studies reported most 0,5% topical

timolol maleate, administered one drop two times a

day resulted in complete regression of superficial

IH, but only a few studies reported the use of lower

concentration (timolol maleate 0,25%) with the same

potential to reduce the lesion. Lower concentration

theoretically further reduce the risk of side effects,

such as hypotension, hypoglycemia, bradycardia,

and bronchoconstriction. (Chambers et al, 2012).

Prior before starting treatment, we examined

complete blood count (include blood glucose),

cardiovascular function, and pulmonary function.

Laboratory test and cardiopulmonary were regular

so that we started the treatment with topical β

blocker. Contraindication for β blocker includes AV

block (grade 2 and 3), congestive heart failure,

bronchospasm, hypoglycemia, hypotension, and

sinus bradycardia. Topical timolol maleate 0,5%

solutions or GSF consider safe treatment for

superficial IH in term infants receiving a dose less

than 0,2 mg/kg/day, with no adverse events reported.

Higher risk for systemic adverse events is

prematurity and low birth weight, baby. Adverse

events of β blocker usually reported by using

systemic propranolol, but only a few or almost no

adverse event reported by using topical β blocker.

Short-term adverse events include hypotension,

bradycardia, and hypoglycemia. Long-term adverse

events include emotional lability, sleep disturbance,

and other effects related to neural depressant effects.

In our case, the patient was a term baby with average

birth weight, and the lesion was superficial, non-

ulcerated, and located in the temporal region so that

the risk for systemic complication consider minimal

or none. Topical application of β blocker have a

higher risk for systemic complication if given on

mucosal surface (ocular, lips, anogenital), ulcerated

IH, and extend large IH. Evaluation of possible

systemic complication accomplished by educating

parents to evaluate sign and symptoms of adverse

events include lethargy, cyanosis, mottled/cold skin,

irritable, tremor, and excessive sweating. Monthly

evaluation of cardiopulmonary function and blood

glucose checks in hospital. In our case, during three

months of treatment, there wereno adverse effects

occur.

4 CONCLUSIONS

This case represents the treatment of superficial non-

complicated successfully, and non-ulcerated IH with

topical β blocker timolol maleate 0,25% eye drops

There were no adverse effects reported in this case.

It suggests an important to determine the effective

treatment for IH based on some points, include

anatomic depth, morphology, and risk for

complication, functional compromise, and

permanent disfigurement. The purpose of initial

administration treatment for superficial IH consider

to reduce the risk of functional compromise such as

ulceration and scar and risk for residual skin

development include telangiectasia, redundant skin,

and fibrofatty tissues.

458

REFERENCES

Callahan AB, Yoon MK. 2012. Infantile Hemangiomas: A

Review. AAO [internet]. [cited 2019 January

29];26:283-91. Available from:

https://www.researchgate.net/publication/255987798_

Infantile_hemangiomas_A_review DOI:

10.1016/j.sjopt.2012.05.004

Chambers CB, Katowitz WR, Katowitz JA, Binenbaum G.

2012. A Controlled Study of Topical 0,25% Timolol

Maleate Gel for the Treatment of Cutaneous Infantile

Capillary Hemangiomas. Ophthal Plast Surg

[internet]. [cited 2019 February 16]; 28(2): 103-6.

Available from:

https://www.ncbi.nlm.nih.gov/pubmed/22410658doi:1

0.1097/IOP.0b013e31823bfffb.

Dickison P, Student M, Christou E, Wargon O. 2011. A

Prospective Study of Infantile Hemangiomas with a

Focus on Incidence and Risk Factors. Pediatr

Dermatol [internet]. [cited 2019 February 20]; 28(6):

663-9. Available from:

www.ncbi.nlm.nih.gov/pubmed/21995808doi:10.1111

/j.15251470.2011.01568.

Haggstrom AN, Beaumont JL, Lai SL, Adams DM, Droet

BA,Frieden IJ, et al. 2012. Measuring the Severity of

Infantile Hemangiomas. Arch Dermatol [internet].

[cited 2019 January 30]; 148(2):197-202. Available

from:

https://www.ncbi.nlm.nih.gov/pubmed/22351819

doi: 10.1001/archdermatol.2011.926.

Laranjo S, Costa G, Parames F, Freitas I, Martins JD,

Trigo C, et al. 2014. The role of propranolol in the

treatment of infantile hemangioma. Rev Port Cardiol

[internet]. [cited 2019 January 28];33(5):289-95.

Available

from:https://www.ncbi.nlm.nih.gov/pubmed/24906291

doi:10.1016/j.repc. 2013.10.018

Moyakine AV, Koulil S, Vleuten CJM. 2017. Propanolol

treatment of infantile hemangioma is not associated

with psychological problems at 7 years of age. J Am

Acad Dermatol [internet]. July. [cited 2019 January

29];105-8. Available from:

https://www.ncbi.nlm.nih.gov/pubmed/28190620

doi: 10.1016/j.jaad.2017.01.025.

Moyakine AV, Herwegen B, Vleuten CJM. 2017. Use of

the hemangioma Severity Scale to facilitate treatment

decisions for infantile hemangiomas. J Am Acad

Dermatol [internet]. August 14. [cited 2019 January

30];77(5):868-73. Available from:

https://www.ncbi.nlm.nih.gov/pubmed/28818436doi:

10.1016/j.jaad.2017.06.003

Painter SL, Hildebrand GD. 2016. Review of topical beta

blockers as treatment for infantile hemangiomas. Surv

Opthalmol [internet]. [cited 2019 January 29];61:51-8.

Available from:

https://www.ncbi.nlm.nih.gov/pubmed/26408055

doi: 10.1016/j.survophthal.2015.08.006.

Paller AS, Mancini AJ. 2016. Hurwitz Clinical Pediatric

Dermatology. Fifth edition. [cited 2019 February 3].

Chicago: Elsevier. pp: 279-95.

Rotter A, Najjar Z, Oliveira P. 2017. Infantile

hemangiomas: pathogenesis and mechanisms of action

of propranolol.JDDG [internet]. [cited 2019 January

29];1185-1190. Available from:

https://www.ncbi.nlm.nih.gov/pubmed/29193649

doi: 10.1111/ddg.13365

Weibel L, Barysch MJ, Scheer HS, Konigs I, Neuhaus K,

Schiestl C, et al. 2016. Topical Timolol for Infantile

Hemangiomas: Evidence for Efficacy and Degree of

Systemic Absorption. Peadtr Dermatol [internet].

[cited 2019 February 7]; 33(2):184-90. Available

from:

https://www.ncbi.nlm.nih.gov/pubmed/26840644

doi: 10.1111/pde.12767.

Zheng JW, Zhou Q, Mai HM, Wang YA, Fan XD, Qin

ZP. 2013. A practical guide to treatment of infantile

hemangiomas of the head and neck. Int J Clin Exp

Med [internet]. [cited 2019 January 31];6(10):851-60.

Available from:

https://www.ncbi.nlm.nih.gov/pubmed/24260591

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