TOPICAL THERAPY

Timolol
Timolol is a non-selective β blocker which is used for increased intra-ocular pressure. In 2010, Guo and Ni first reported the clinical response to timolol 0.5% solution in a 4-month-old infant who had a thin haemangioma plaque on the upper eyelid.[48] Subsequently, several pilot studies and case series have shown its clinical efficacy.[49505152] It has been mostly used for localized, non-ulcerated superficial IHs. Chan et al. found timolol to be more effective for lesions with a mean diameter of <11.3 mm (i.e. 100 mm3 in volume) as compared to larger lesions.[53] It is to be applied two times a day. One drop of timolol maleate (0.5%) contains 0.25 mg of the drug.[53] It is recommended to apply 1 drop of the gel two times a day. Some authors recommend 3-4 times application.[52] Timolol does not penetrate deeply and hence it is not useful in deep haemangiomas.[52] Treatment is more effective in the proliferative phase than in the involution phase, and also, plaques respond better than nodules.[53]
Recently, the safety and efficacy of topical timolol has been studied in a blinded, randomized, placebo-controlled trial. The medications (topical timolol maleate gel 0.5% and placebo) were applied (1 drop) twice daily for 24 weeks. The response was periodically assessed. The authors observed that there was a significant improvement in absolute volume reduction, proportional growth and clinical appearance after 12-16 weeks of timolol therapy compared to the placebo group. No significant side effects were reported. The authors suggested that 2 drops per day application of topical timolol maleate 0.5 % gel is safe and effective therapy for IH which does not require systemic medications.[53]

Propranolol
Topical propranolol 1% ointment has been used successfully in the treatment of superficial IHs, especially as an adjuvant therapy during the wait-and-watch period. Kunzi-Rapp et al. in their series of 45 cases of superficial haemangiomas, used propranolol 1% ointment locally twice daily.[54] Of the 65 haemangiomas treated, 59% showed regression and 26% had cessation of growth. In 15% of the cases, no response was seen. Concomitant use of propranolol ointment with pulsed dye laser (PDL) in two of their cases of ulcerated haemangioma led to healing of ulcers in 3 and 6 weeks, respectively. In a retrospective chart review by Xu et al., 16 (57%) out of 28 haemangiomas demonstrated good response, 9 (33%) showed partial response and 3 (10%) had no response.[55] No side-effects have been reported so far.

Imiquimod
Imiquimod, an immune response modifier with anti-angiogenic and pro-apoptotic properties, has been used in the treatment of superficial IH. Imiquimod 5% cream is applied on alternate days at bed time and left for 8 hours. It is washed with mild soap the next morning. The duration of therapy is about 4 months. Severe inflammatory reactions may occur with application of imiquimod. Qiu et al. studied the efficacy and safety of imiquimod in their retrospective comparative study of imiquimod versus timolol in superficial proliferative IH. They found that the efficacy of imiquimod was comparable with timolol. However, inflammatory changes were seen in 13 of 20 (65%) cases in the imiquimod group while none of cases in the timolol group had side effects.[56]

Topical steroids
Potent steroids have been used to treat flat or minimally raised vascular plaques of IH particularly at sites prone to ulcerations and disfigurement. Described adverse effects include localised atrophy, hypopigmentation, hypertrichosis and infections. Garzon et al. retrospectively studied the clinical effects and safety of ultrapotent topical corticosteroids (clobetasol propionate 0.05% in 27 infants, betamethasone dipropionate 0.05% in 4 and halobetasol propionate in 3 cases) in 34 children. The treatment was given for a period ranging from 4 weeks to 21 weeks. They found that 35% showed good response, 38% partial response and 27% no response. The authors found good safety profile for lesions at all sites, including the peri-ocular region.[57] Following the successful reports of topical timolol, topical steroids are less often prescribed in the current practice.

Other modalities

Pulsed Dye Laser (PDL)
PDL has been used successfully for the treatment of ulcerated IH, which reduces the pain and promotes healing.[58] It is also used to remove the residual telangiectasia. However, the use of PDL in uncomplicated IH is controversial. There are non-randomized studies which claim that PDL is better than the wait-and-watch policy.[5960] In a large prospective RCT by Batta et al., 121 children with uncomplicated early haemangiomas were assigned to PDL (585 nm) treatment or observation.[61] At the end of 1 year, there was no significant differences between the 2 groups (60 in PDL group, 61 in observation group) in terms of complete clearance or residual features. The adverse effects were significantly more in the PDL group which led the authors to conclude that PDL is no better than observation in uncomplicated superficial IH.[61] In another recent prospective RCT on 22 infants, the intervention group was treated with PDL (595 nm). The authors did not observe any difference in echo depth or surface area at 1 year between the intervention (n = 11) and observation groups (n = 11). However, the cosmetic outcome was significantly better in the PDL group.[62] In a comparative study between traditional PDL (585 nm) and long PDL (LPDL; 595 nm), the authors found that a similar number of infants achieved complete clearance or showed minimal residual signs at 1 year of age (14/26, 54% in PDL group vs. 17/26, 65% in LPDL group; P = 0.4), although the infants in LPDL group suffered significantly less side-effects like hypo- or hyperpigmentation, textural changes and the period of maximal proliferation was also significantly shortened (106 days in LPDL versus 177 days in PDL group).[63]
There is no consensus on the optimal settings of PDL and selection of type of haemangiomas suitable for treatment with laser. Currently, the use of PDL is confined to the treatment of ulceration and post-involution erythema and telangiectasias.[64]

Other lasers
Frequency-doubled Nd:YAG laser was found to be less effective than PDL in a retrospective study on 50 infants with superficial IH.[65] In another study, the use of sequential 595-nm PDL followed by 1064-nm Nd:YAG laser led to excellent response in 18 (72%) out of 25 infants with IH on skin and mucous membrane in the head and neck region.[66] Good results with intralesional therapy using KTP laser have been described in treating voluminous haemangiomas.[67]
The level of evidence with respect to studies using various treatment modalities is given in Table 3.
Table 3  Level of evidence: Therapeutic modalities*

Congenital haemangiomas
These are fully formed haemangiomas at birth. There are two sub-types: Rapidly involuting congenital haemangiomas (RICH) and non-involuting congenital haemangiomas (NICH). In both the forms, the proliferative phase occurs in utero. Unlike IH, these are GLUT 1 negative tumours. They manifest as erythematous to violaceous large hemispherical tumours and a peripheral halo of pallor. The surface may show telangiectasia. RICH completely involutes by 12-18 months of age [Figure 4a and 4b]. NICH lesions do not involute over time [Figure 4c and 4d] and hence may require surgical excision or embolization.
Figure 4  (a and b) Congenital haemangioma, (a) RICH at 1 month, (b) after resolution at 7 months of age, (c and d) NICH (courtesy of Anthony J Mancini)