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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 16
| Issue : 1 | Page : 75-81 |
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Treatment outcomes of oral propranolol in the treatment of periocular infantile capillary hemangioma and factors predictive of recurrence and incomplete resolution: A multi-centric study
Sweety Tiple1, Prajakta Kimmatkar2, Sima Das1, Alankrita Muralidhara2, Nehashree2, Ayush Mehta3, Narendra Patidar3, Elesh Jain3
1 Oculoplasty and Ocular Oncology Services, Dr. Shroff's Charity Eye Hospital, New Delhi; Bodhya Eye Consortium, India
2 Oculoplasty and Ocular Oncology Services, Dr. Shroff's Charity Eye Hospital, New Delhi, India
3 Bodhya Eye Consortium; Orbit and Oculoplasty Services, Sadguru Netra Chikitsalaya, Chitrakoot, Madhya Pradesh, India
| Date of Submission | 08-Jan-2022 |
| Date of Decision | 06-Sep-2022 |
| Date of Acceptance | 10-Dec-2022 |
| Date of Web Publication | 21-Feb-2023 |
Correspondence Address:
Sima Das
Oculoplasty and Ocular Oncology Services, Dr. Shroff's Charity Eye Hospital, 5027, Kedarnath Road, Daryaganj, New Delhi - 110 002
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ojo.ojo_11_22
 Abstract | | |
AIM: This study aims to evaluate the treatment outcomes of periocular capillary hemangioma with oral propranolol (OP) and list the factors predictive of recurrence and incomplete resolution after treatment.
METHODOLOGY: Data were collected by retrospective review of medical files of patients with infantile hemangioma (IH) treated with OP during January 2014–December 2019 from two tertiary eye institutes from India. Patients presenting with symptoms of IH with/without any history of prior treatment were included. All patients were started on OP with the dose of 2–2.5 mg/Kg body weight and continued till complete resolution or till the lesion reached a plateau response. Details about the ophthalmic examination at each visit and availability of imaging findings were noted down from the records. Primary outcome: Study the treatment outcome of patients treated with OP and discussed our observations regarding factors that may predict nonresponse, poor response, or recurrence. Secondary outcome: complications/side effects of therapy. Response to treatment was judged as fair, good, and excellent depending on resolution <50%, >50%, and complete resolution, respectively. Univariate analysis of factors related to treatment response was judged as fair, good, and excellent depending on resolution <50%, >50%, outcome and recurrence was studied using Mann–Whitney U test and Fisher's exact test.
RESULTS: A total of 28 patients were included in the study, out of which 17 were female and 11 were male. The mean age of onset of the lesion was 1.08 (± 1.484) months, 11 being congenital in origin. The mean age at presentation was 4.15 (± 2.92) months. 46.43% (n = 13) of patients showed complete resolution, while 25% (n = 7) showed more than 50% reduction in lesion size. Fair response was noted in 28.57% (n = 8). The mean duration of follow-up after stopping OP was 17.7 (± 20.774) months. The recurrence rate noted was 14.28%. The factors which were associated with incomplete resolution were age at presentation >3 months, later age of appearance of the lesion, superficial lesions with no orbital involvement. Male gender and congenital lesions responded best to OP therapy. Minor complications were noted with a rate of 25% (n = 7). Younger age at presentation was more commonly associated with complications.
CONCLUSION: OP is a safe and effective treatment for capillary hemangioma except for a smaller subset of patients who show suboptimal response to this drug. However, specific factors responsible for suboptimal response or recurrence after OP therapy remain elusive. Although not statistically significant, there was an increasing trend toward higher age at presentation, low birth weight, and superficial lesions with a poorer response. Furthermore, these factors along with the male gender were commonly associated with recurrence in our series. Larger prospective studies focused on evaluating clinical factors responsible for incomplete resolution and recurrence will help in prognosticating and suggesting alternative treatment regimes.
Keywords: Capillary hemangioma, infantile hemangioma, propranolol
How to cite this article:
Tiple S, Kimmatkar P, Das S, Muralidhara A, Nehashree, Mehta A, Patidar N, Jain E. Treatment outcomes of oral propranolol in the treatment of periocular infantile capillary hemangioma and factors predictive of recurrence and incomplete resolution: A multi-centric study. Oman J Ophthalmol 2023;16:75-81 |
How to cite this URL:
Tiple S, Kimmatkar P, Das S, Muralidhara A, Nehashree, Mehta A, Patidar N, Jain E. Treatment outcomes of oral propranolol in the treatment of periocular infantile capillary hemangioma and factors predictive of recurrence and incomplete resolution: A multi-centric study. Oman J Ophthalmol [serial online] 2023 [cited 2023 Mar 27];16:75-81. Available from: https://www.ojoonline.org/text.asp?2023/16/1/75/370028 |
| Introduction | |  |
Infantile hemangioma (IH) are common, benign self-limited vascular tumors of infancy, having an incidence of 4%–5%.[1],[2],[3] They constitute the most common benign vascular ocular tumors in the pediatric age group.[4] IH has a well-defined natural history, classically manifest as a rapid proliferative phase in the first three months of birth followed by spontaneous involution phase, which lasts for several years.[5],[6] Congenital hemangiomas (CH) are rarer and usually present as fully grown lesions at birth with minimal change in the size of the lesion after birth.[7],[8] Large prospective studies on demographics of IH found female gender, Caucasian ethnicity, prematurity, low birth weight (LBW), multiple gestations, and advanced maternal age as risk factors.[2],[4],[5] Diagnosis is mainly clinical. However, Doppler ultrasound and contrast magnetic resonance imaging (MRI) of the orbit is considered standard investigations for defining the extent of the lesion and also for defining the endpoint of the treatment.[9],[10] Despite the self-limiting course, the treatment is specifically warranted in vision-threatening amblyopia due to occlusion of the visual axis, disfigurement, or complications like necrosis or bleeding from the lesion.
Although the etiopathogenesis of IH remains obscure, factors such as angiogenesis and vasculogenesis, germline or somatic mutation, and even genetic factors have been attributed to it.[3],[8],[11] Oral propranolol (OP) is now considered the first-line drug in the nonsurgical management of IH with dramatic results within the first 48 h of starting therapy. Propranolol is a nonselective beta-blocker with a possible mechanism of vasoconstriction, inhibition of angiogenesis, and induction of apoptosis in proliferating endothelial cells.[8] Effect on the renin-angiotensin system and VEGF suppression have also been demonstrated as the possible mechanism.[3],[11] Side effects of OP include hypotension, hypoglycemia, bradycardia, pulmonary hyperreactivity, and transient symptoms such as sleep disturbance, daytime drowsiness, and gastroenteritis.
Although there is significant literature on the role of propranolol and its related complications/side effects in IH affecting other parts of the body, the literature regarding periocular IH treated with OP is limited.[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] There is no definitive consensus regarding the duration of therapy as the rate of rebound growth of the lesion after stopping treatment has been reported to be 10%–30%.[27],[28],[29] Although the success of OP therapy is quite high, cases with no or poor response to OP after the initial few weeks have also been illustrated in the literature. The factors which might affect prognosis in IH, the role of these factors in nonresponders/rebound or recurrent tumors after completion of treatment, is not well understood. The objective of this series is to report the outcome of OP therapy in our subset of patients and to report factors which commonly affected the outcome, especially with regards to incomplete resolution/recurrence which will help in prognosticating the outcome and planning alternate treatment.
| Methodology | | |
A retrospective observational study was conducted from two tertiary eye care centers as part of Bodhya eye consortium. Data were collected by reviewing the medical files of consecutive patients of infantile capillary hemangioma treated with OP from January 2014 to December 2019. Informed consent was obtained from the guardians of the patients after explaining the pros and cons of the treatment. The study was approved by the institutional review board of the two centers and also by the scientific committee of the consortium and adhered to the declaration of Helsinki.
Selection criteria
Children with periocular/orbital capillary hemangioma presenting at birth or a few weeks after birth who received OP with/without a history of any other previous treatment (oral/intralesional steroids/surgery) for the same were included. All patients after termination of therapy with a minimum follow-up of 3 months following complete/partial resolution/nonresponse to therapy were included in the study.
Exclusion criteria
Patients with onset of the lesion after 3 years of age, noncompliance to treatment, or those with insufficient follow-up were excluded from the study.
Demographic data (age, gender, gestational history, and age at presentation of symptoms), lesion characteristics, imaging (computed tomography [CT] scan/MRI orbit, wherever available), age at the beginning of treatment, OP dosage, and duration were collected from the medical record. The treatment was started on an outpatient department basis with an average dose of 2–2.5mg/Kg body weight in two divided doses 12 h apart and monitored by an experienced pediatrician, after a thorough pretreatment evaluation. Patients were regularly followed up as per protocol by the pediatrician and the treating ophthalmologist.
Response to treatment was assessed clinically in terms of decrease in size of the lesion (including change in color and texture of the overlying skin). Photographic documentation was done at least on the first and the final visit. Once IH had regressed completely or entered a plateau phase (no further response noted), OP was tapered over 2 weeks and stopped. Response to treatment was graded as excellent, good, fair, and poor based on clinical evaluation by the treating ophthalmologist as the percentage of resolution from the original lesion. The results were graded as excellent on the complete resolution of the visible lesion; good when more than 50% reduction of the lesion, fair when less than 50% reduction in size/no growth of the lesion, and poor when continued growth or intolerable adverse effects was noted. Nonresponders were defined as those showing no response to OP after 4–6 weeks. Recurrence/rebound lesion was defined as the reappearance of the lesion partly or completely to its original size within a minimum of 1 month after stopping OP.
Statistical analysis was performed using the software R version 4.0.3. Descriptive data (demographic features etc.) are presented as mean (±standard deviation) (Mann–Whitney test). Univariate analysis of patient factors with relation to the treatment outcome was done. Continuous data such as age of appearance of the lesion, age at presentation and starting therapy, duration of OP use, and follow-up after stopping therapy were compared using Mann–Whitney test, and discrete data like gestational factors, lesion characteristics were compared using Fisher's exact test to test the significance of difference. A P < 0.05 was considered statistically significant.
| Results | | |
A total of 29 eyes of 28 patients were included in the study with 11 being male and 17 being female. The mean age at presentation was 4.15 months (±2.92). Twenty-four babies (85.71%) were born at full term with only four being pre-term. Eleven (39.28%) were LBW. Twenty-one (75%) were delivered normally, while 7 babies were born of cesarean section. None of the babies in our series were born of in vitro fertilization. Twenty-one children were able to fix and follow the light, however, in 7 patients' vision was not documented. Mean age-onset was 1.08 months (±1.484). Thus, out of the total 28 patients, 17 (60.71%) were IHs, and the remaining 11 (39.29%) were CH.
None of the patients had received any prior treatment/surgery before the presentation. Fourteen (50%) had right eye involvement, 13 had left eye involvement while one patient had bilateral involvement. Eyelid involvement was noted in 27 eyes. Mechanical ptosis due to the involvement of the upper eyelid was the most common presentation (n = 20), followed by proptosis (n = 9) due to orbital involvement. Pure orbital involvement was noted in only one patient. Superficial lesions were noted in 5 (17.86%), deep lesions in 13 (46.42%), and combined lesions were noted in 10 (35.71%) babies. CT scan of the orbit was done in 50% (n = 14), however, documentation was available in only 25% (n = 7) of the patients. On CT scan, combined preseptal with orbital mass was noted in 6 babies. Superior orbit was most commonly involved (n = 4). Out of the orbital lesions, intraconal lesions amounted 42.86%, extraconal lesions amounted 57.14%. Five (17.85%) had associated hemangiomas on other body parts.
All the patients were advised OP immediately at presentation. Two babies in author' s series who had presented with a massive lesion or had bleeding/necrosis received a short course (4 weeks in tapering dose) of oral steroids simultaneously, to hasten the resolution. Those patients were not included for analysis as part of this study to avoid the confounding effect of the steroid on the resolution of hemangioma. OP was stared as 2 mg/kg body weight in two divided doses. The average duration of OP was 8.44 (± 4.709) months. 46.43% (n = 13) patient showed excellent response [Figure 1], while 25% (n = 7) showed good response [Figure 2]. The fair response was noted in 28.57% (n = 8) [Figure 3]. Poor response was not noted in our series. The average duration of follow-up was 19.44 (±17.247) months. Six patients were still on OP till their last visit. The mean duration of follow-up after stopping OP in the remaining patients was 17.7(± 20.774) months. In patients who showed an incomplete response, two underwent intralesional steroids injection and two required excision biopsies with lid reconstruction for the residual lesion. Four (14.28%) patients who were noncompliant, came back with a recurrence. The average age at which recurrence was noted was 2.25 months after stopping treatment. All 4 cases with recurrence showed incomplete resolution with only approx. 50% reduction in the lesion size even after resuming treatment. | Figure 1: Right upper lid capillary hemangioma (a), shows resolution with oral propranolol (b)
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 | Figure 2: Left upper lid and orbital capillary hemangioma (a), showing minimal residual after 8 months of oral propranolol treatment (b)
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 | Figure 3: Capillary hemangioma over left eye medial canthal area with fair outcome pre (a), and posttreatment with oral propranolol (b)
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The results with regards to resolution (excellent/good/fair/poor) have been depicted in [Table 1] and those with regards to recurrence in [Table 2]. | Table 1: Relationship of different factors to the clinical outcome of infantile hemangioma
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 | Table 2: Relationship of different factors to the recurrence of infantile hemangioma
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The factors which were found more commonly associated with fair response (incomplete recovery) were age at presentation >3 months (45.5%, P = 0.516), later age of appearance of the lesion (P = 0.181), superficial lesions (60%, P = 0.107) with no orbital involvement. Delay in starting OP could not be compared as a predictable factor as only two patients had a delay of more than 3 months and both resolved completely. The duration of follow-up and duration of use of OP was significantly higher in patients with the fair response for obvious reasons. Male gender and congenital lesions responded best to OP therapy.
Recurrence was noted to be more common in babies presenting at a younger age (<3 months), male gender (30%) as compared to female, infantile rather than the congenital lesion. Furthermore, LBW babies with normal term deliveries were shown to have more recurrence. Superficial lesion (40%, P = 0.084) without orbital involvement showed more recurrence. The mean duration at the use of OP in this subset was 14 (±3.4) months (P = 0.022) as due to the recurrence, the patients were treated for a longer duration of time with a total follow-up of 30.5(± 18.4) months (P = 0.144).
A complication rate of 25% (n = 7) was noted in our study. They included minor systemic symptoms possibly attributed to propranolol treatment such as stomach pain, upper respiratory infection and bronchial hyperreactivity, and peri-oral rash. These complications were noted in the younger age group with a mean of 3.4 months (P = 0.648). Complications resolved without need for admission.
| Discussion | | |
Periocular capillary hemangioma of infancy is a common benign vascular tumor of infancy with a predictable clinical self-limiting course. Female's gender (60.7%), LBW (39.28%) babies are more commonly affected as was seen in our series. However, full-term babies delivered normally were more commonly found in our series. Seventeen babies (60.71%) had IHs, the rest 39.29% patients had lesions noticed at birth. Approximately 65% of patients of IH are known to have precursor lesions in the form of localized telangiectasia/erythema/bruise at birth.[6] However, CH are fully developed at birth. Confirmation regarding the exact nature of these congenital lesions based on history could not be made due to the retrospective nature of the study and records had to be relied upon.
The diagnosis was made based on clinical examination and imaging was done only in suspected orbital lesions to confirm the location and the extent. Although CT scan has been used as the imaging modality for most patients in the current series primarily due to the cost constraint and the issues with the availability of the imaging facility, MRI with contrast is the recommended orbital imaging modality for these patients. Most of the studies evaluating the response to OP use subjective clinical evaluation as a percentage of resolution of the lesion from the original lesion, as was done in our series, and may involve observation bias. Chang et al. suggested using color Doppler ultrasound as an effective way of documenting response, the guide for discontinuation of treatment, and also to eliminate observation bias.[30]
We saw the dramatic effect of OP within the first 2 days of starting therapy in most of our patients as has been reported in the literature. The rate of resolution is variable in several studies, partial resolution (60%–85%) being higher than complete resolution (25%–40%).[17],[18],[19],[20],[21],[22],[31],[32],[33] In our series, complete resolution was noted in 46.43% while >50% reduction in size was noted in 25%. 28.57% showed a reduction <50% of the original lesion. OP is found to be most effective during the first 3 months of age (proliferative stage). However, the mean age at which the patients presented to us was 4.15 months (± 2.92) which was beyond the age at which treatment is reported to be most effective, which was also found to be the single most important factor (P = 0.496) associated with incomplete resolution in our series. The role of the pediatrician in the diagnosis and early referral cannot be overstressed.
OP is indicated in the deeper, orbital lesion; however, an incomplete resolution was noted in superficial lesions with no orbital involvement in our patients. Excellent outcome was obtained in patients with earlier age at the appearance of the lesion, early initiation of therapy, congenital rather than infantile type lesion, patients treated with a dose of 2mg/Kg and lesions involving the left eye, due to some unexplained reason. We had a high response rate which was comparable to the literature. Response to OP based on the lesion morphology on biopsy, presence of certain receptors (GLUT-1), absence of action against β3 adrenoreceptors found in the lesion, and ultrasound and MRI characteristics of the lesion have been described in the prediction of outcome to OP.[4],[11],[12] Size and extent of lesion, deeper lesion due to their delayed presentation and longer proliferative phase are known to respond less, however, we found superficial lesion to be less responsive to OP, again pointing towards multiple factors which may play a role in the outcome.
The rate of recurrence/rebound growth following discontinuation of treatment either after complete resolution or in between during treatment has been reported to be 10%–30%.[31],[32],[33] The low recurrence rate in our series (14.28%) could be attributed to the smaller sample size. Many of the factors like LBW, superficial IHs seen in the recurrence subgroup were also commonly found in the partial resolution subgroup, as observed by Chang et. al. who suggested that recurrence can be expected in patients who respond slowly, to begin with.[29],[30] IH is a female-dominant condition, however, male gender and lower age at presentation showed more chances of recurrence.
Although there is no consensus over the exact dose or duration of OP, the dose of 2mg/Kg was found to be effective in our series. Literature suggests gradual tapering of OP over 2-week after complete resolution or at 12 months' age (whichever is later), or if no change is noted during 3 months of follow-up.[28] The chances of recurrence are proposed to be more if OP is stopped suddenly before 1 year of age.[29],[32] However, in our study, all the four patients with recurrence had received OP even after 1 year of age and still had a recurrence, suggesting that abrupt termination of therapy and slow response, to begin with, may have been responsible. The final response of these four patients even after resuming therapy was fair.
Complications although rare in our series were noted more commonly in younger babies as also proposed by Ji et al. who in their univariate analysis suggested that younger age, premature birth, and low body weight were associated with more side effects.[22],[34]
Despite the small sample size in our series, we made a few observations relating to the age of appearance of the lesion (congenital/infantile), age at presentation to the hospital, gestational factors, nature of the lesion (superficial/deep, preseptal/orbital) duration for which OP was administered, which although did not achieve a statistically significant value. A systematic review by Spiteri Cornish et al. includes studies with a maximum sample size of eighteen babies.[18] Even in the recent literature on periocular IH, the maximum sample size was thirty, indicating the rarity of the condition further reiterating that despite the smaller sample size our observations cannot be simply ignored as irrelevant clinically.[9],[19],[22]
We suggest larger multicentric studies with a bigger sample size to further reinforce our findings regarding the outcome of OP therapy and the factors responsible for it. This will not only help in predicting prognosis at the beginning of treatment but also help in planning alternative therapies in babies who have the red flags pointing towards possible suboptimal response to propranolol. Furthermore, the role of the pediatrician in the timely referral of IH cases to a specialist for treatment may lead to a better response.
| Conclusion | | |
OP is a safe and effective treatment for periocular IH and CH. Higher age at presentation, low birth weight and superficial lesion had a trend towards suboptimal response although no statistical significance was reached for these factors. In addition to these factors, male gender was more commonly associated with recurrence though none of these associations reached a statistical significance.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]
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